3-(6-alkoxy-5-chlorobenzo[d]isoxazol-3-yl)propanoic acid useful as kynurenine monooxygenase inhibitors

ABSTRACT

Compound of formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein: 
             R 1  is heteroaryl either unsubstituted or substituted by methyl, ethyl, halo or ═O; and 
             R 2  is H, methyl or ethyl;
 
and salts thereof are KMO inhibitors and may be useful in the treatment of various disorders, for example acute pancreatitis, chronic kidney disease, acute kidney disease, acute kidney injury, other conditions associated with systemic inflammatory response syndrome (SIRS), Huntington&#39;s disease, Alzheimer&#39;s disease, spinocerebellar ataxias, Parkinson&#39;s disease, AIDS-dementia complex, HIV infection, amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lung injury, acute respiratory distress syndrome, acute cholecystitis, severe burns, pneumonia, extensive surgical procedures, ischemic bowel, severe acute hepatic disease, severe acute hepatic encephalopathy or acute renal failure.

FIELD OF THE INVENTION

The present invention relates to 5-chlorobenzo[d]isoxazole compounds,processes for their preparation, pharmaceutical compositions comprising5-chlorobenzo[d]isoxazole compounds and to their use in the treatment ofvarious conditions or disorders such as acute pancreatitis and otherconditions or disorders mediated by KMO.

BACKGROUND OF THE INVENTION

Kynurenine monooxygenase (KMO) is a flavin adenine dinucleotide (FAD)dependent monooxygenase located on the outer mitochondrial membrane. KMOis known to oxidise L-kynurenine (KYN) to 3-hydroxykynurenine (3HK) aspart of the major route of catabolism of tryptophan. 3HK is thenconverted to 3-hydroxyanthranilic acid and quinolinic acid bykynureninase (KYNU) and 3-hydroxyanthranilate 3,4-dioxygenase (3-HAAO).

KMO is highly expressed in tissues including the liver, placenta, kidney[Alberati-Giani, FEBS Lett. 410:407-412(1997)], endothelial cells andmonocytes and at a lower level in microglia and macrophages in thebrain.

Increased levels of 3HK and quinolinic acid and reduced levels ofkynurenic acid (KYNA), which is formed from kynurenine by an alternativepathway, have been implicated in a number of diseases includingHuntington's Disease, Parkinson's Disease, Alzheimer's Disease,amyotrophic lateral sclerosis (ALS) [Amaral, Outeiro et Al. Journal ofMolecular Medicine 2013: 91(6): 705-713] and acute pancreatitis [Mole,McFerran et al. British Journal of Surgery 2008: 95: 855-867]. In theCNS 3-HK and quinolinic acid have been shown to be neurotoxic and KYNAto have neuroprotective effects. Inhibition of KMO oxidative activitywould therefore be expected to result in reduced levels of 3-HK andquinolinic acid and increased levels of KYNA and to potentially showbenefit in these diseases.

There is a large body of evidence showing that tryptophan metabolism isalso altered in a range of acute injury settings. For instance,increased kynurenine levels have been associated with the development ofsepsis following trauma [Pellegrin, 2005, Logters, 2009], whileincreased levels of both kynurenine and 3-HK correlate with thedevelopment of organ failure in acute pancreatitis [Mole, McFerran etal. British Journal of Surgery 2008: 95: 855-867]. This dysregulation oftryptophan metabolism is in part accounted for by the induction ofindolamine 2,3 dioxygenase (IDO, the enzyme that converts tryptophan toN-formyl kynurenine) as part of the inflammatory cascade, but thedevelopment of organ dysfunction appears dependent on the downstreammetabolites [Mole, McFerran et al. British Journal of Surgery 2008: 95:855-867].

Acute pancreatitis (AP) results from local injury to the organ driven byfactors such as excessive alcohol consumption or gallstones. The arisingabdominal pain is extremely severe, and patients will invariably presentto an emergency department rapidly following onset of an attack, withelevation of serum amylase used as a diagnostic measure. In the majorityof cases, the disease is self-limiting, and the pain is resolved within24-36 hours. However for the remaining 20-30% of patients a systemicinflammatory response occurs, resulting in rapid progression to multipleorgan dysfunction (MOD). This leads to a prolonged stay in an intensivecare unit (ICU), averaging 17 days, with a mortality rate of over 30%.Despite this high unmet need and the seriousness of the disease, thereare no effective treatments available, with current standard of carebeing purely supportive.

WO2013016488, WO2011091153, WO2010017132, WO2010017179, WO2010011302,WO2008022286 and WO2008022281 describe inhibitors of KMO for targetingneurodegenerative disorders or diseases. EP1475385, EP1424333 describeinhibitors of KMO for targeting degenerative and inflammatoryconditions. There remains a need for KMO inhibitors for use in thetreatment various conditions or disorders mediated by KMO such as acutepancreatitis and other conditions associated with systemic inflammatoryresponse syndrome (SIRS). WO2015091647 discloses5-chlorobenzo[d]oxazol-2(3H)-one derivatives as inhibitors of KMO.

A class of compounds has now been found which are inhibitors of KMO.Inhibitors of KMO may be useful in the treatment of various conditionsor disorders such as, for example, acute pancreatitis and acuteconditions associated with systemic inflammatory response syndrome(SIRS).

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I):

wherein R¹ and R² are as defined below;

or a salt thereof.

Certain compounds have been shown to be KMO inhibitors. Compounds whichinhibit KMO may be useful in the treatment of various disorders, forexample acute pancreatitis, chronic kidney disease, acute kidneydisease, acute kidney injury, other conditions associated with systemicinflammatory response syndrome (SIRS), Huntington's disease, Alzheimer'sdisease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementiacomplex, HIV infection, amylotrophic lateral sclerosis (ALS),depression, schizophrenia, sepsis, cardiovascular shock, severe trauma,acute lung injury, acute respiratory distress syndrome, acutecholecystitis, severe burns, pneumonia, extensive surgical procedures,ischemic bowel disease, severe acute hepatic disease, severe acutehepatic encephalopathy or acute renal failure.

Accordingly, the invention is further directed to methods of treatmentof a condition or disorder mediated by KMO, which methods compriseadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

The invention is further directed to a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient.

The invention is further directed to a compound of formula (I) or apharmaceutically acceptable salt thereof for use in therapy.

The invention is further directed to the use of a compound of formula(I) or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for the treatment of a disorder or condition mediated byKMO.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, there are provided compounds of formula (I):

wherein:

R¹ is unsubstituted heteroaryl or heteroaryl substituted by methyl,ethyl, halo or ═O; and

R² is H, methyl or ethyl.

or a salt thereof.

In one embodiment, R¹ is a 5-membered heteroaryl comprising one nitrogenatom or one oxygen atom and further comprising a nitrogen atom, or a6-membered heteroaryl comprising one, two or three nitrogen atoms,wherein said heteroaryl is unsubstituted or substituted by methyl,ethyl, halo or ═O.

In one embodiment, R¹ is selected from the group consisting of oxazolyl,pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl; wherein the oxazolyl,pyrazolyl, pyridyl, pyridazinyl, and pyrimidinyl may be unsubstituted orsubstituted by methyl, ethyl, halo or ═O.

In one embodiment, R¹ is selected from the group consisting ofunsubstituted oxazolyl, and pyridyl, pyridazinyl, and pyrimidinyl;wherein the pyridyl, pyridazinyl, and pyrimidinyl may be unsubstitutedor substituted by methyl, halo or ═O.

In one embodiment, R¹ is selected from the group consisting ofunsubstituted oxazolyl, pyridyl, pyridazinyl, and pyrimidinyl; whereinthe pyridyl and pyrimidinyl may be unsubstituted or substituted bymethyl, halo or ═O and the pyridazinyl may be unsubstituted orsubstituted by methyl or ═O.

In one embodiment, R¹ is selected from the group consisting of oxazolyl,pyridyl, pyridazinyl, and pyrimidinyl; wherein the oxazolyl, pyridylpyridazinyl and pyrimidinyl may be unsubstituted or substituted bymethyl, halo or ═O.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 3-oxazolyl, 3, pyrazolyl, 2-pyridyl, 3-pyridazinyl, and2-pyrimidinyl; wherein the 2-oxazolyl, 3-oxazolyl, 2-pyridyl,3-pyridazinyl, and 2-pyrimidinyl may be unsubstituted or substituted bymethyl, halo or ═O, and the 3-pyrazolyl may be unsubstituted orsubstituted by ethyl.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridazinyl, and 2-pyrimidinyl;wherein the 2-oxazolyl, 2-pyridyl, 3-pyridazinyl, and 2-pyrimidinyl maybe unsubstituted or substituted by methyl, halo or ═O.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridazinyl, and2-pyrimidinyl; wherein the 2-oxazolyl may be unsubstituted orsubstituted by methyl or ethyl, 5-oxazolyl may be unsubstituted orsubstituted by ethyl, 3-pyrazolyl may be unsubstituted or substituted byethyl, 2-pyridyl may be unsubstituted or substituted by methyl, ethyl,halo or ═O, the 3-pyridazinyl may be unsubstituted or substituted bymethyl, and the 2-pyrimidinyl may be unsubstituted or substituted bymethyl or halo.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 2-pyridyl, 3-pyridazinyl, and 2-pyrimidinyl; wherein the2-pyridyl may be unsubstituted or substituted by methyl, halo or ═O andthe 3-pyridazinyl may be unsubstituted or substituted by methyl.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 2-pyridyl, 3-pyridazinyl, and 2-pyrimidinyl; wherein the2-pyridyl may be unsubstituted or substituted by methyl, or halo and the3-pyridazinyl may be unsubstituted or substituted by methyl.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 2-pyridyl, 3-pyridazinyl, and 2-pyrimidinyl; wherein the2-pyridyl may be unsubstituted or substituted by methyl, chloro orfluoro and the 3-pyridazinyl may be unsubstituted or substituted bymethyl.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 2-pyridyl, 5-methyl-2-pyridyl, 5-chloro-2-pyridyl,5-fluoro-2-pyridyl, 3-pyridazinyl, 6-methyl-3-pyridazinyl5-ethyl-2-pyridyl, 6-ethyl-2-pyridyl, 5-chloro-2-pyrimidinyl,5-methyl-2-pyrimidinyl, 2-methyl-1,3-oxazol-5-yl,4-ethyl-1,3-oxazol-2-yl, 1-ethyl-1H-pyrazol-3-yl, 5-chloro-2-pyrimidinyland 2-pyrimidinyl.

In one embodiment, R¹ is selected from the group consisting of2-oxazolyl, 2-pyridyl, 5-methyl-2-pyridyl, 5-chloro-2-pyridyl,5-fluoro-2-pyridyl, 3-pyridazinyl, 6-methyl-3-pyridazinyl and2-pyrimidinyl.

In one embodiment, R¹ is unsubstituted or substituted pyridyl.

In one embodiment, R¹ is 2-pyridyl.

In one embodiment, R¹ is unsubstituted or substituted pyridazinyl.

In one embodiment, R¹ is substituted pyridazinyl.

In one embodiment, R¹ is methylpyridazinyl.

In one embodiment, R¹ is 6-methylpyridazin-3-yl.

In one embodiment, R² is H.

In one embodiment, R² is methyl.

In one embodiment, R¹ is 2-pyridyl and R² is methyl.

In one embodiment, R¹ is 6-methylpyridazin-3-yl and R² is methyl.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid; or a salt thereof.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid-   3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid; and-   3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;

or a salt thereof

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid-   3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid; and-   3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-{5-chloro-6-[1-(3-fluoropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;

or a salt thereof

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid (racemic);-   3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   diol    3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;

or a salt thereof.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;

and

-   (S)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;

or a salt thereof.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid (racemic);-   3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   diol    3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   3-{5-chloro-6-[(1R)-1-(3-fluoropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;

or a salt thereof

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid (racemic);-   3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   diol    3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   and-   (S)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid (racemic);-   3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   diol    3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   3-{5-chloro-6-[(1R)-1-(3-fluoropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)    propanoic acid, tris(hydroxymethyl)aminomethane) salt;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with sulfuric acid (1:1);-   sodium    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with (S)-2-amino-5-guanidinopentanoic acid (1:1);-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with (S)-2,6-diaminohexanoic acid (1:1);-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid hydrochloride;-   (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentanol    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with methanesulfonic acid (1:1);-   N-benzyl-2-phenylethanamine    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   N¹,N²-dibenzylethane-1,2-diamine    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate    (1:2);-   N¹-(2-aminoethyl)ethane-1,2-diamine    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate    (1:3);-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with 4-methylbenzenesulfonic acid (1:1);-   2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid (racemic); 2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   (R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

(R)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoicacid;

-   (S)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   (S)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid.

In one embodiment, the compound of formula (I) is selected from the listconsisting of:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)    propanoic acid,-   tris(hydroxymethyl)aminomethane) salt;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with sulfuric acid (1:1);-   sodium    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with (S)-2-amino-5-guanidinopentanoic acid (1:1);-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with (S)-2,6-diaminohexanoic acid (1:1);-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid hydrochloride;-   (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentanol    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with methanesulfonic acid (1:1);-   N-benzyl-2-phenylethanamine    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   N¹,N²-dibenzylethane-1,2-diamine    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate    (1:2);-   N¹-(2-aminoethyl)ethane-1,2-diamine    (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate    (1:3);-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid compound with 4-methylbenzenesulfonic acid (1:1);-   2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid (racemic);-   2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   2-amino-2-(hydroxymethyl)propane-1,3-diol    (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate;-   (R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (R)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid; and-   (S)-3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoic    acid.-   (R)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (S)-3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoic    acid;-   (R)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   (S)-3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid;-   and-   3-{5-chloro-6-[(1R)-1-(3-fluoropyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoic    acid.

In one embodiment, the compound of formula (I) is:

-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid or a salt thereof.

In one embodiment, the compound of formula (I) is:

-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is:

-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid.

In one embodiment, the compound of formula (I) is:

-   3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid in the form of a pharmaceutically acceptable salt.

In one embodiment, the compound of formula (I) is:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid or a salt thereof.

In one embodiment, the compound of formula (I) is:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid.

In one embodiment, the compound of formula (I) is:

-   (R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic    acid in the form of a pharmaceutically acceptable salt.

In one embodiment, the compound of formula (I) is3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a salt thereof.

In one embodiment, the compound of formula (I) is3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid.

In one embodiment, the compound of formula (I) is3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid in the form of a pharmaceutically acceptable salt.

In one embodiment, the compound of formula (I) is(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a salt thereof.

In one embodiment, the compound of formula (I) is(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid.

In one embodiment, the compound of formula (I) is(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid in the form of a pharmaceutically acceptable salt.

In one embodiment, the pharmaceutically acceptable salt is anethanolamine salt.

Terms and Definitions

Compounds of formula (I) and salts thereof are referred to hereinafteras “Compounds of the invention”.

The term “halogen” or “halo” as used herein refers to fluorine (F),chlorine (CI), bromine (Br), or iodine (I). Examples of suitablehalogens are fluorine and chlorine.

The term “heteroaryl” as used herein refers to a 5- or 6-memberedaromatic ring which comprises one or more (e.g. 1, 2 or 3) heteroatomsindependently selected from O, N or S. For example, when “heteroaryl”represents a 5-membered ring, the ring contains a heteroatom selectedfrom O, N or S and may optionally contain 1 to 3 further nitrogen atoms(e.g. may further contain one, two or three nitrogen atoms). When“heteroaryl” represents a 6-membered ring, the ring may contain from 1to 3 nitrogen atoms. Examples of such 5- or 6-membered heteroaryl ringsinclude, but are not limited to, pyrrolyl, triazolyl, thiadiazolyl,tetrazolyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl,oxazolyl, oxadiazolyl, furazanyl, furanyl, thienyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl.

‘Enantiomeric excess’ (ee) is the excess of one enantiomer over theother expressed as a percentage. In a racemic modification, since bothenantiomers are present in equal amounts, the enantiomeric excess iszero (0% ee). However, if one enantiomer were enriched such that itconstitutes 95% of the product, then the enantiomeric excess would be90% ee (the amount of the enriched enantiomer, 95%, minus the amount ofthe other enantiomer, 5%).

‘Enantiomerically enriched’ refers to products whose enantiomeric excess(ee) is greater than zero. For example, ‘enantiomerically enriched’refers to products whose enantiomeric excess is greater than 50% ee,greater than 75% ee, and greater than 90% ee.

‘Enantiomerically pure’ refers to products whose enantiomeric excess is99% or greater.

Included within the scope of the compounds of the invention are allsolvates (including hydrates), complexes, polymorphs, radiolabelledderivatives, and stereoisomers of the compounds of formula (I) and saltsthereof.

Included within the scope of the compounds of the invention are allsolvates (including hydrates), complexes, polymorphs, prodrugs,radiolabelled derivatives, and stereoisomers of the compounds of formula(I) and salts thereof.

Prodrugs of the compounds of the invention are included within the scopeof the present invention. In one embodiment, the compounds of theinvention are not prodrugs.

As used herein, the term “prodrug” means a compound which is convertedwithin the body, e.g. by hydrolysis in the blood, into its active formthat has medical effects. Pharmaceutically acceptable prodrugs aredescribed in T. Higuchi and V. Stella, Prodrugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987 and in D. Fleishner, S. Ramon andH. Barba “Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs”, Advanced Drug Delivery Reviews (1996) 19(2)115-130. Prodrugs are any covalently bonded carriers that release acompound of formula (I) in vivo when such prodrug is administered to apatient. Prodrugs are generally prepared by modifying functional groupsin a way such that the modification is cleaved in vivo yielding theparent compound. Prodrugs may include, for example, compounds of theinvention wherein the carboxylic acid group is bonded to any group that,when administered to a patient, cleaves to form the carboxylic acidgroup. Thus, representative examples of prodrugs include (but are notlimited to) phosphonate, carbamate, acetate, formate and benzoatederivatives of the carboxylic acid functional group of the compounds ofthe invention.

The compounds of the invention are capable of forming base additionsalts. Such salts can be formed by reaction with the appropriate base,optionally is a suitable solvent such as an organic solvent, to give thesalt which can be isolated by crystallisation and filtration.

The compounds of the invention are also capable of forming acid additionsalts. Such salts can be formed by reaction with the appropriate acid,optionally in a suitable solvent such as an organic solvent, to give thesalt which can be isolated by crystallisation and filtration.

It is to be understood that the references herein to compounds offormula (I) and salts thereof covers the compounds of formula (I) asfree bases, free acids or as salts thereof, for example aspharmaceutically acceptable salts thereof. Thus, in one embodiment, theinvention is directed to compounds of formula (I) as the free base. Inanother embodiment, the invention is directed to compounds of formula(I) as the free acid. In another embodiment, the invention is directedto compounds of formula (I) and salts thereof. In a further embodiment,the invention is directed to compounds of formula (I) andpharmaceutically acceptable salts thereof.

Because of their potential use in medicine, it will be appreciated thatfor use in medicine the salts of the compounds of the invention shouldbe pharmaceutically acceptable. As used herein the term‘pharmaceutically acceptable salts’ refers to salts that retain thedesired biological activity of the subject compound and exhibit minimalundesired toxicological effect. Pharmaceutically acceptable salts willbe apparent to those skilled in the art and include those described inBerge, J. Pharm. Sci., 1977, 66, 1-19.

Pharmaceutically acceptable base salts include, but are not limited to,ammonium salts, alkali metal salts such as those of sodium andpotassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases, including salts of primary,secondary and tertiary amines, such as t-butylamine, cyclohexylamine,dimethylamine, trimethylamine, diethyltriamine,2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), ethanolamine andN-methyl-D-glucamine.

Pharmaceutically acceptable base addition salts include, but are notlimited to, ammonium salts, alkali metal salts such as those of sodiumand potassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases, including salts of primary,secondary and tertiary amines, such as t-butylamine, cyclohexylamine,dimethylamine, trimethylamine, diethyltriamine,2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), ethanolamine, cholineand N-methyl-D-glucamine.

Pharmaceutically acceptable acid salts include, but are not limited to,hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate,sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate,propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate,acrylate, fumarate, malate, tartrate, citrate, salicylate,p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate,succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate,formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate,malonate, laurate, glutarate, glutamate, estolate, methanesulfonate(mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate,benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate(tosylate), napthalene-2-sulfonate, ethanedisulfonate, and2,5-dihydroxybenzoate.

Pharmaceutically acceptable acid addition salts include, but are notlimited to, hydrochloride, hydrobromide, nitrate, methylnitrate,sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate,phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate,hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate,salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate,phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate,palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate,glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate(esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate),p-aminobenzenesulfonate, p-toluenesulfonate (tosylate),napthalene-2-sulfonate, ethanedisulfonate, and 2,5-dihydroxybenzoate.

In one embodiment, the salt is a pharmaceutically acceptable salt.

In one embodiment, the pharmaceutically acceptable salt is anethanolamine salt.

Certain compounds of the invention are capable of existing insterioisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of these compounds and themixtures thereof including racemates. The different stereoisomeric formsmay be separated one from the other by methods known in the art (e.g.separation by chiral HPLC) or any given stereoisomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof.

Certain compounds of the invention may contain an asymmetric centre(also referred to as a chiral centre) and may, therefore, exist asindividual enantiomers, or as mixtures thereof. Where thestereochemistry of a chiral centre present in formula (I), or in anychemical structure illustrated herein, is not specified, the structureis intended to encompass any stereoisomer and all mixtures thereof.Thus, compounds according to formula (I) containing one or more chiralcentres may be used as racemic modifications including racemic mixturesand racemates, enantiomerically-enriched mixtures, or asenantiomerically-pure individual stereoisomers.

Individual stereoisomers of a compound according to formula (I) whichcontain one or more asymmetric centres may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. It will be appreciated thatwhere the desired stereoisomer is converted into another chemical entityby one of the separation procedures described above, a further step isrequired to liberate the desired form. Alternatively, specificstereoisomers may be synthesised by asymmetric synthesis using opticallyactive reagents, substrates, catalysts or solvents, or by converting oneenantiomer to the other by asymmetric transformation.

In one aspect, there is provided a compound of formula (I) wherein R₂ isnot H, and wherein the (R) enantiomer is present in greater than 90%enantiomeric excess (“ee”).

In one embodiment, the (R) enantiomer is present in greater than 95% ee.

In one embodiment, the (R) enantiomer is present in greater than 99% ee.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).

Certain compounds of the invention may exist in the form of solvates. Asused herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. If the solvent used is water, the solvate maybe referred to as a hydrate.

It will be further appreciated that certain compounds of the inventionthat exist in crystalline form, including the various solvates thereof,may exhibit polymorphism (i.e. the capacity to occur in differentcrystalline structures). These different crystalline forms are typicallyknown as ‘polymorphs’. The invention includes such polymorphs.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. It will be appreciatedthat different polymorphs may be produced, for example, by changing oradjusting the reaction conditions or reagents, used in making thecompound. For example, changes in temperature, pressure, or solvent mayresult in polymorphs. In addition, one polymorph may spontaneouslyconvert to another polymorph under certain conditions.

Compounds of formula (I) and salts thereof may be isotopically-labelledand as such are identical to compounds of the invention, but for one ormore atoms having been replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number most commonly foundin nature. Examples of isotopes that can be incorporated into compoundsof the invention are isotopes of hydrogen, carbon, nitrogen, fluorine,such as ³H, ¹¹C, ¹⁴C and ¹⁸F. Such isotopically-labelled compounds areuseful in drug and/or substrate tissue distribution assays. For example,¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emissiontomography). PET is useful in brain imaging. Isotopically labelledcompounds of the invention can generally be prepared by carrying out theprocedures disclosed below, by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

ABBREVIATIONS

conc. concentrated

DCM dichloromethane

DEAD diethylazodicarboxylate

DMF N,N-dimethylformamide

DMSO dimethylsulphoxide

ESI electrospray ionisation

h hour(s)

HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid

HOBt 1-hydroxybenzotriazole

HPLC high performance liquid chromatography

LCMS liquid chromatography-mass spectrometry

MeCN acetonitrile

min minutes

mL millilitre

Ms/mesyl methanesulphonyl

NMR nuclear magnetic resonance

R-CBS (R)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole

RT room temperature

Rt retention time

SFC supercritical fluid chromatography

THF tetrahydrofuran

TFA trifluoroacetic acid

TRIS 2-amino-2-(hydroxymethyl)-1,3-propanediol

Compound Preparation

Compounds of the invention (wherein R¹ and R² are as hereinbeforedefined) may be synthesised substantially according to Reaction Scheme 1by treatment of ethyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (IIIa) (a compoundof formula (III) wherein R is ethyl) or methyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (IIIb) (a compoundof formula (III) wherein R is methyl) with CH(R¹)(R²)OMs of formula (IV)in the absence of coupling reagents, or with CH(R¹)(R²)OH of formula (V)in the presence of coupling reagents, followed by the saponification oracid-mediated hydrolysis of the resultant ester of formula (II).

The alkyl 3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoates offormula (III) can be synthesised substantially according to ReactionSchemes 2 and 3 starting from 4-chlororesorcinol.

The mesylate CH(R¹)(R²)OMs of formula (IV) can be synthesised from theracemic alcohol of formula (V), obtained from reduction of the aldehydeor ketone of formula (VI), substantially according to Reaction Scheme 4(to produce racemic activated alcohol) or from the chiral alcohol offormula (V) obtained from chiral deduction of the ketone of formula (VI)substantially according to Reaction Scheme 5 (to produce chirallyenriched activated alcohol)

Alternatively, the mesylate of formula (IV) can be synthesisedsubstantially according to Reaction Scheme 6 from the carboxylic acid offormula (IX). Treatment of the carboxylic acid of formula (IX) withN,O-dimethylhydroxylamine in the presence of suitable coupling agents,for instance HOBT and EDCl, to afford the Weinreb amide of formula(VII), followed by treatment with the Grignard reagent of formula (VIII)affords the ketone of formula (VI). Reduction of the ketone of formula(VI) with a suitable reducing agent, for instance sodium borohydride(NaBH₄) affords the achiral alcohol (V), which may be optionallyactivated, for instance as the mesylate of formula (IV) by introductionof a suitable activating group, for instance mesylate, by treatment withan activating agent, for instance by treatment with mesyl chloride(MsCI), in a suitable solvent, for instance dichloromethane (DCM), usinga suitable base, for instance triethylamine (Et₃N), at a suitabletemperature, for instance ambient temperature.

Alternatively, the mesylate of formula (IV) may be synthesisedsubstantially according to Reaction Scheme 7, by treatment of the cyanocompound of formula (X) with a Grignard reagent of formula (VIII) in asuitable solvent, for instance THF, at a suitable temperature, forinstance 0° C., to afford the ketone or aldehyde of formula (VI).

Reduction of the aldehyde or ketone of formula (VI) under achiralconditions, for instance using sodium borohydride (NaBH₄) in a suitablesolvent, for instance methanol (MeOH), affords the achiral alcohol offormula (V).

Reduction of the ketone of formula (VI) (R₂ is not H) under chiralconditions, for instance using R-CBS((R)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole) andborane-dimethylsulphide in a suitable solvent, for instance THF, affordsthe chiral alcohol (VA).

The achiral alcohol of formula (V) or chiral alcohol of formula (VA) maybe optionally activated, for instance as the corresponding mesylate offormula (IV) or formula (IVA) by introduction of a suitable activatinggroup, for instance mesyate, by treatment with an activating agent, forinstance by treatment with mesyl chloride (MsCl), in a suitable solvent,for instance dichloromethane (DCM), using a suitable base, for instancetriethylamine (Et₃N), at a suitable temperature, for instance ambienttemperature.

It will be appreciated by those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques, suchas those described in “Greene T. W. Protective groups in organicsynthesis, New York, Wiley (1981)”, can be used. For example, primaryamines can be protected as phthalimide, trifluoroacetyl, benzyl,tert-butyloxycarbonyl, benzyloxycarbonyl or trityl derivatives.Carboxylic acid groups can be protected as esters. Aldehyde or ketonegroups can be protected as acetals, ketals, thioacetals or thioketals.Deprotection of such groups is achieved using conventional procedureswell known in the art. For example, protecting groups such astert-butyloxycarbonyl may be removed using an acid such as hydrochloricor trifluroroacetic acid in a suitable solvent such as dichloromethane,diethylether, 1,4-dioxane, isopropanol or mixtures thereof.

For any of the hereinbefore described reactions or processes,conventional methods of heating and cooling may be employed, for exampletemperature-regulated oil-baths or temperature-regulated hot-blocks, andice/salt baths or dry ice/acetone baths respectively. Conventionalmethods of isolation, for example extraction from or into aqueous ornon-aqueous solvents may be used. Conventional methods of drying organicsolvents, solutions, or extracts, such as shaking with anhydrousmagnesium sulfate, or anhydrous sodium sulfate, or passing through ahydrophobic frit, may be employed. Conventional methods of purification,for example crystallisation and chromatography, for example silicachromatography or reverse-phase chromatography, may be used as required.Crystallisation may be performed using conventional solvents such asethyl acetate, methanol, ethanol, or butanol, or aqueous mixturesthereof. It will be appreciated that specific reaction times andtemperatures may typically be determined by reaction-monitoringtechniques, for example thin-layer chromatography and LCMS.

General Methods

Unless stated otherwise, starting materials were commercially available.All solvents and commercial reagents were of laboratory grade and wereused as received.

Where diasteroisomers are represented and only the relativestereochemistry is referred to, or where an enantiomer is representedand the absolute stereochemistry is unknown, the bold or hashed solidbond symbols are used (

). Alternatively, where diasteroisomers are represented and only therelative stereochemistry is referred to, or where an enantiomer isrepresented and the absolute stereochemistry is unknown, the use of“or1” at the chiral centre denotes that the absolute stereochemistry ofthe particular compound is unknown, i.e. the compound as drawn may beeither the R enantiomer or the S enantiomer. Where the absolutestereochemistry is known and the compound is a single enantiomer, thebold or hashed wedge symbol (

) are used as appropriate, without the use of “or1” at the chiralcentre.

Analytical Methods

LCMS Methods

Method Description A Column: Acquity BEH C18 (50 mm × 2.1 mm, 1.7 μm)Mobile Phase: A: 0.1% Formic acid in water; B: 0.1% Formic acid in MeCNTime (min)/% B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3 Column Temp:35° C. Flow Rate: 0.6 mL/min B Column: Acquity BEH C18 (50 mm × 2.1 mm,1.7 μm) Mobile Phase: A: 0.1% Formic acid in water; B: 0.1% Formic acidin MeCN Time (min)/% B: 0/3, 1.5/100, 1.9/100, 2/3. Column Temp: 40° C.Flow Rate: 1.0 mL/min C Column: X Bridge C18 (50 mm × 4.6 mm, 2.5 μm)Mobile Phase: C: MeCN; D: 5 mM Ammonium Acetate in water Time (min)/% C:0/5, 0.5/5, 1/15, 3.3/98, 5.2/98, 5.5/5, 6/5. Column Temp: 35° C. FlowRate: 1.3 mL/min D Column: X Bridge C18 (50 mm × 4.6 mm, 2.5 μm) MobilePhase: A: 5 mM Ammonium bicarbonate in water (pH~10); B: MeCN Time(min)/% B: 0/5, 0.5/5, 1/15, 3.3/98, 5.2/98, 5.5/5, 6/5. Column Temp:35° C. Flow Rate: 1.3 mL/min E Column: Acquity BEH C18 (100 mm × 2.1 mm,1.7 μm) Mobile Phase: A: 0.1% TFA in water; B: 0.1% TFA in MeCN Time(min)/% B: 0/2, 8.5/99, 9.5/99, 9.6/2, 10.5/2, 10.01/3. Column Temp: 50°C. Flow Rate: 0.5 mL/min

LCMS Method I

Agilent 1200-6110,

Signal table: Signal A: 214 nm, Signal B: 254 nm;

Column Temperature: 40° C.

Column: HALO C18 4.6*50 mm, 2.7 μm

Solvents Gradient Polarity Solvent A: H₂O 0.00 min: A: 95.0% B: 5.0%Positive (0.1% formic acid) 1.00 min: A: 5.0% B: 95.0% Solvent B: CH₃CN2.00 min: A: 5.0% B: 95.0% (0.1% formic acid) 2.01 min: A: 95.0% B: 5.0%2.50 min: A: 95.0% B: 5.0%

HPLC Method

Method Description F Column: XBridge C18 (150 mm × 4.6 mm, 3.5 μm)Mobile Phase: A: 10 mM Ammonium Acetate in water; B: 100% MeCN Time(min)/% B: 0/5, 1.5/5, 3/15, 7/55, 10/95, 14/95, 17/5, 20/5. ColumnTemp: 35° C. Flow Rate: 1.0 mL/min Diluent: 70:30 (MeCN:H₂O)

Chiral SFC Method

Method Description G Column: CHIRALPAK IA (250 mm × 4.6 mm, 5 μm)Eluent: A: CO₂ = 60%; B: Methanol = 40%; Back pressure: 100 bar; Temp:26° C. Flow Rate: 4 g/min H Column: CHIRALPAK AD-H (250 mm × 4.6 mm, 5μm) Eluent: A: CO₂ = 60%; B: 0.5% DEA in methanol = 40%; Back pressure:100 bar; Temp: 26° C. Flow Rate: 5 g/min

Chiral SFC Data

Enantiomeric Chiral Chiral Purity Retention excess (% SFC Example no.(%) Time (min) ee) Method  1i 99.99 1.82 99.99 G  3 99.35 1.64 100 H  499.49 16.61 99.31 H  9 99.82 1.73 99.64 H  8 99.90 12.81 99.81 H 1199.95 1.48 99.90 H 12 99.50 2.97 99.00 H 14 99.02 4.32 98.66 H 15 98.442.18 97.81 H

The names of the intermediates and examples have been obtained using thecompound naming programme within “ChemBioDraw Ultra v12”, oralternatively using “ACD Name Pro 6.02”.

INTERMEDIATES Intermediate 1: 1-(5-chloro-2,4-dihydroxyphenyl)ethanone

To a stirred solution of 4-chlororesorcinol (30.0 g, 208.3 mmol) inboron trifluoride diethyl ether complex (150 mL) was added glacialacetic acid (20 mL) drop wise at 0° C. The reaction mixture was heatedto 80° C. and maintained for 2 days. After complete consumption of thestarting material, the reaction mixture was cooled, poured into 10%aqueous sodium acetate solution and stirred for 1 h. The solidprecipitated was filtered, dried under vacuum for 1 h, washed withdiethyl ether and dried under vacuum to afford1-(5-chloro-2,4-dihydroxyphenyl)ethanone (18.0 g, 47%) as an off-whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.32 (s, 1H), 11.39 (s, 1H), 7.88 (s, 1H),6.47 (s, 1H), 2.55 (s, 3H); LCMS (ESI): m/z 185/187 [M−H]⁻; Rt=1.83 min;method A.

Intermediate 1a (Intermediate 1 Alternative Preparation):1-(5-chloro-2,4-dihydroxyphenyl)ethanone

To a stirred solution of 4-chlororesorcinol (1.0 Kg, 6.92 mol) in borontrifluoride diethyl ether complex (4 L) was added glacial acetic acid(411 mL). The reaction mixture was heated at 80° C. with stirring for 2days. After complete consumption of the starting material, the reactionmixture was cooled to 0° C., poured into 10% aqueous sodium acetatesolution and stirred for 12 h. The solid precipitated was isolated byfiltration, washed with diethyl ether (100 mL) and dried under vacuum(˜44 h) to afford 1-(5-chloro-2,4-dihydroxyphenyl)ethanone (860 g, 66%)as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 12.46 (s, 1H), 7.70 (s, 1H), 6.60 (s, 1H),6.00 (s, 1H), 2.56 (s, 3H); LCMS (ESI): m/z 185/187 [M−H]⁻; Rt=2.80 min;method C.

Intermediate 2: 1-(5-chloro-2-hydroxy-4-methoxyphenyl)ethanone

To a stirred solution of 1-(5-chloro-2,4-dihydroxyphenyl)ethanone (forexample as prepared for Intermediate 1) (6.0 g, 32.2 mmol) in acetone(100 mL) was added potassium carbonate (5.11 g, 37.0 mmol) andmaintained at RT for 10 min. To this, dimethyl sulfate (3.07 mL, 32.2mmol), was added and allowed to stir at RT for 2 days. After completeconsumption of the starting material, the reaction mixture was filteredand the filtrate concentrated under reduced pressure to afford thecrude, which was purified by silica gel (100-200 mesh) columnchromatography using 3% ethyl acetate in petroleum ether to afford1-(5-chloro-2-hydroxy-4-methoxyphenyl)ethanone (4.20 g, 65%) as a whitesolid.

¹H NMR (400 MHz, CDCl₃): δ 12.65 (s, 1H), 7.69 (s, 1H), 6.48 (s, 1H),3.93 (s, 3H), 2.56 (s, 3H); LCMS (ESI): m/z 199/201 [M−H]⁻; Rt=1.05 min;method B.

Intermediate 2a (Intermediate 2 alternative preparation)1-(5-chloro-2-hydroxy-4-methoxyphenyl)ethanone

To a stirred solution of 1-(5-chloro-2,4-dihydroxyphenyl)ethanone (forexample as prepared for Intermediate 1a) (860 g, 4.61 mol) in acetone (5L) were added potassium carbonate (763 g, 5.53 mol) and dimethyl sulfate(446 mL, 4.61 mol) at 0° C. and allowed to stir at RT for 2 days. Aftercompletion of the starting material, the reaction solution was filteredand concentrated under reduced pressure. The crude product was purifiedby triturated with 10% DCM in hexane (1.5 L; stirred for 1 h at 10° C.).The solid obtained was filtered, washed with hexane and dried undervacuum to afford 1-(5-chloro-2-hydroxy-4-methoxyphenyl)ethanone (800 g,86%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.52 (s, 1H), 7.94 (s, 1H), 6.69 (s, 1H),3.91 (s, 3H), 2.58 (s, 3H); LCMS (ESI): m/z 199/201[M−H]⁻; Rt=3.62 min;method D.

Intermediate 3: 6-chloro-4-hydroxy-7-methoxy-2H-chromen-2-one

To a stirred solution of sodium hydride (60% in mineral oil; 7.4 g, 187mmol) in toluene (300 mL) was added a solution of1-(5-chloro-2-hydroxy-4-methoxyphenyl)ethanone (for example as preparedfor Intermediate 2) (13.0 g, 65 mmol) in toluene (200 mL). After 30 min,diethyl carbonate (15.3 g, 130 mmol) was added and warmed to 120° C. for2 days. After completion of the reaction, the reaction mixture wasdiluted with water and extracted with ethyl acetate. The separatedaqueous layer was acidified with dilute hydrochloric acid solution topH-2. The precipitated solid was filtered and dried under vacuum toafford 6-chloro-4-hydroxy-7-methoxy-2H-chromen-2-one (9.0 g, 61%) as awhite solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.56 (s, 1H), 7.76 (s, 1H), 7.20 (s, 1H),5.49 (s, 1H), 3.95 (s, 3H); LCMS (ESI): m/z 227/229 [M⁺]; Rt=0.85 min;method B.

Intermediate 3a (Intermediate 3 alternative preparation):6-chloro-4-hydroxy-7-methoxy-2H-chromen-2-one

To a stirred solution of sodium hydride (60% in mineral oil; 246.5 g,6.16 mol) in toluene (1 L) was added a solution of1-(5-chloro-2-hydroxy-4-methoxyphenyl)ethanone (for example as preparedfor Intermediate 2a) (300 g, 1.49 mol) in toluene (1 L) under inertatmosphere. After 30 min at 10° C., diethyl carbonate (292 mL, 2.41 mol)was added at 10° C. The reaction mixture was heated and stirred at 100°C. for 24 h. After completion of the reaction, the solution was allowedto cool to RT, diluted with ice-cold water and acidified with 6N aqueoushydrochloric acid (to pH-2). The solid precipitate was filtered anddried under vacuum to afford6-chloro-4-hydroxy-7-methoxy-2H-chromen-2-one (300 g, 88%) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.60 (bs, 1H; D₂O exchangeable), 7.76 (s,1H), 7.19 (s, 1H), 5.50 (s, 1H), 3.95 (s, 3H); LCMS (ESI): m/z 227/279[M⁺]; Rt=1.93 min; method A.

Intermediate 4: 2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetic acid

To a freshly prepared solution of sodium ethoxide in ethanol (3.05 g ofsodium metal dissolved in ethanol (200 mL)) was added hydroxylaminehydrochloride (9.1 g, 131.1 mmol) and6-chloro-4-hydroxy-7-methoxy-2H-chromen-2-one (for example as preparedfor Intermediate 3) (3.0 g, 13.2 mmol) under inert atmosphere. Thereaction was stirred and heated at reflux (95° C.) for 6 days. Aftercomplete conversion of the starting material, the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dilutedwith water, washed with ethyl acetate and then acidified with dilutehydrochloric acid solution (up to pH-1). A solid precipitated wasfiltered and dried under vacuum to afford2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetic acid (2.0 g, 62%) asan off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 12.91 (s, 1H), 7.97 (s,1H), 7.55 (s, 1H), 4.05 (s, 2H), 3.97 (s, 3H); LCMS (ESI): m/z 242/244[M⁺]; Rt=1.82 min; method A.

Intermediate 4a (Intermediate 4 Alternative Preparation):2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetic acid

To a stirred solution of hydroxylamine hydrochloride (143 g, 2.20 mol)in ethanol (1.5 L) was added sodium ethoxide (150 g, 2.20 mol) at 0-10°C. under inert atmosphere. To this,6-chloro-4-hydroxy-7-methoxy-2H-chromen-2-one (for example as preparedfor Intermediate 3a) (100 g, 441.3 mmol) was added at same temperature.The reaction mixture was heated at ˜80° C. and stirred for 16 h. Aftercomplete conversion of the starting material, the reaction mixture wasconcentrated under reduced pressure. The obtained residue was dilutedwith water. The resultant solution was acidified with 2N hydrochloricacid (up to pH˜2) and stirred for 1 h. The solid precipitate wasfiltered and dried under vacuum (˜4 h) to afford2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetic acid (60 g, 56%) as anoff-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.85 (s, 1H; D₂O exchangeable), 7.95 (s,1H), 7.53 (s, 1H), 4.04 (s, 2H), 3.97 (s, 3H); LCMS (ESI): m/z 242/244[M+H⁺]; Rt=2.24 min; method C.

Intermediate 5: methyl2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetate

To a stirred solution of2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetic acid ((for example asprepared for Intermediate 4) (2.0 g, 8.2 mmol) in methanol (100 mL) wasadded a solution of conc. sulphuric acid (2 mL) in methanol (100 mL) atRT and heated to reflux and then maintained for 4 h. After completeconsumption of the starting material, the reaction mixture wasconcentrated under reduced pressure. The obtained residue wasneutralized with saturated aqueous NaHCO₃ solution and extracted withethyl acetate. The combined organic extracts were dried over anhydroussodium sulfate and concentrated under reduced pressure to afford methyl2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetate (2.0 g, 95%) as abrown solid.

¹H NMR (400 MHz, CDCl₃): δ 7.69 (s, 1H), 7.07 (s, 1H), 3.99 (m, 5H),3.77 (s, 3H); LCMS (ESI): m/z 256/258 [M⁺]; Rt=2.15 min; method A.

Intermediate 6: 2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethanol

To a stirred solution of lithium aluminium hydride (15.6 mL, 1M in THFsolution) was added a solution of methyl2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetate ((for example asprepared for Intermediate 5) (2.0 g, 7.8 mmol) in THF (100 mL) at 0° C.The reaction was allowed to warm to RT and stirred for 4 h. Aftercomplete consumption of the starting material, the reaction mixture wasquenched with ethyl acetate followed by aqueous sodium sulfate solutionover a period of 30 min. The resultant heterogeneous mixture wasfiltered through a Celite™ pad. The organic layer was separated, driedover anhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by silica gel (100-200 mesh) columnchromatography using 25% ethyl acetate in petroleum ether to afford2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethanol (0.8 g, 44%) as anoff-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.01 (s, 1H), 7.49 (s, 1H), 4.86 (t, J=5.3Hz, 1H; D₂O exchangeable), 3.96 (s, 3H), 3.80 (td, J=6.4, 5.3 Hz, 2H),3.06 (t, J=6.4 Hz, 2H); LCMS (ESI): m/z 228/230 [M+H⁺]; 94.1%; Rt=2.94min; method C.

Intermediate 6a (Intermediate 6 Alternative Preparation):2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethanol

To a stirred solution of ethyl2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetate (for example asprepared for Intermediate 14) (60 g, 223 mmol) in ethanol (1.3 L) andTHF (300 mL) was added sodium borohydride (16.87 g, 446 mmol) at 0° C.under inert atmosphere. The reaction was heated at 60-70° C. for 4 h.After complete consumption of the starting material, the volatiles wereremoved under reduced pressure to obtain the residue. The residue wasdiluted with ice-cold water and extracted with ethyl acetate (3×500 mL).The combined organic extracts were washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford the crude product, which was purified by trituration with pentaneand hexane to afford 2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethanol(44.3 g, 88%) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.01 (s, 1H), 7.49 (s, 1H), 4.85 (t, J=5.3Hz, 1H; D₂O exchangeable), 3.96 (s, 3H), 3.80 (td, J=6.3, 5.1 Hz, 2H),3.06 (t, J=6.3 Hz, 2H); LCMS (ESI): m/z 228/230 [M+H⁺]; Rt=3.31 min;method D.

Intermediate 7: 2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethylmethanesulfonate

To a stirred solution of2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethanol (for example asprepared for Intermediate 6) (0.8 g, 3.5 mmol) in DCM (60 mL) was addedmesyl chloride (0.32 mL, 4.2 mmol) and triethylamine (1.82 mL, 14.0mmol) at 0° C. The reaction was allowed to warm to RT and stirred for 16h. After completion, the reaction mixture was diluted with water. Theorganic layer was separated, dried over anhydrous sodium sulfate andevaporated under reduced pressure to afford2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethyl methanesulfonate (1.0g, crude) as an off-white solid, which was directly taken for nextreaction without purification.

¹H NMR (400 MHz, DMSO-d₆): δ 8.11 (s, 1H), 7.54 (s, 1H), 4.61 (t, J=6.0Hz, 2H), 3.96 (s, 3H), 3.40 (t, J=6.0 Hz, 2H), 3.16 (s, 3H).

Intermediate 7a (Intermediate 7 Alternative Preparation):2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethyl methanesulfonate

To a stirred solution of2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethanol (for example asprepared for Intermediate 6a) (44.3 g, 195.1 mmol) in DCM (520 mL) wasadded triethylamine (78.8 g, 780.6 mmol) and mesyl chloride (44.4 g,390.3 mmol) at 0° C. The reaction was stirred for 16 h. After completionof the reaction, the reaction mixture was diluted with water andextracted with ethyl acetate. The combined organic extracts were driedover anhydrous sodium sulfate and evaporated under reduced pressure toafford the crude product, which was purified by trituration with hexaneto afford 2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethylmethanesulfonate (54 g, 90%) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.09 (s, 1H), 7.53 (s, 1H), 4.61 (t, J=6.3Hz, 2H), 3.97 (s, 3H), 3.41 (t, J=6.3 Hz, 2H), 3.16 (s, 3H); LCMS (ESI):m/z 306/308 [M+H⁺]; Rt=3.27 min; method C.

Intermediate 8:3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanenitrile

To a stirred solution of2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethyl methanesulfonate (forexample as prepared for Intermediate 7) (1.0 g, 3.27 mmol) in DMSO (100mL) was added sodium cyanide (1.6 g, 32.7 mmol) at RT. The reaction washeated to 100° C. and stirred for 2 h. After consumption of the startingmaterial, the reaction mixture was cooled and poured into ice-cold water(100 mL). The resultant solution was extracted with ethyl acetate. Thecombined organic extracts were dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude product was washed withdiethyl ether to afford3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanenitrile (498 mg, 64%)as an off-white solid.

LCMS (ESI): m/z 237/239 [M+H⁺]; Rt=3.29 min; method C.

Intermediate 8a (Intermediate 8 Alternative Preparation)3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanenitrile

To a stirred solution of2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)ethyl methanesulfonate (forexample as prepared for Intermediate 7a) (220 g, 721.3 mmol) in DMSO(1.5 L) was added NaCN (176.7 g, 3.606 mol) at RT. The reaction washeated at 80° C. and for 4 h. After consumption of the startingmaterial, the reaction mixture was diluted with ice-cold water and theresultant solution extracted with ethyl acetate. The combined organicextracts were dried over anhydrous sodium sulfate and evaporated underreduced pressure. The crude product was washed with n-pentane to afford3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanenitrile (154 g, 90%)as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.11 (s, 1H), 7.54 (s, 1H), 3.97 (s, 3H),3.30 (t, J=7.2 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H); LCMS (ESI): m/z237[M+H⁺]; Rt=3.49 min; method D.

Intermediate 9: 3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoicacid

To a stirred solution of3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanenitrile (for exampleas prepared for Intermediate 8) (600 mg, crude) in ethanol (10 mL) andwater (2 mL) was added sodium hydroxide (508 mg, 12.7 mmol). Thereaction mixture was stirred at reflux for 16 h. After completion of thereaction, the reaction mixture was concentrated under reduced pressure.The residue obtained was diluted with water and washed with ethylacetate. The aqueous layer was acidified with diluted hydrochloric acid(up to pH-2) and extracted with ethyl acetate. The combined organicextracts were washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoic acid (500 mg, 77%)as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (bs, 1H; D₂O exchangeable), 8.05 (s,1H), 7.50 (s, 1H), 3.96 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.76 (t, J=7.3Hz, 2H); LCMS (ESI): m/z 256/258 [M+H⁺]; Rt=1.92 min; method A.

Intermediate 9a (Intermediate 9 Alternative Preparation):3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoic acid

To a stirred solution of3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanenitrile (for exampleas prepared for Intermediate 8a) (154 g, 652.5 mmol) in ethanol (1.4 L)was added a solution of NaOH (130.5 g, 3.262 mol) in water (840 mL) at0° C. The reaction mixture was heated at 80° C. for 16 h. Aftercompletion of the reaction, the mixture was evaporated under reducedpressure. The residue obtained was diluted with ice-cold water andacidified with diluted hydrochloric acid (up to pH-2). The resultantsolution was extracted with ethyl acetate, the combined organic extractswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford a solid., This was triturated with petroleum ether toafford 3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoic acid (160 g,96%) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (s, 1H; D₂O exchangeable), 8.05 (s,1H), 7.50 (s, 1H), 3.96 (s, 3H), 3.15 (t, J=7.3 Hz, 2H), 2.76 (t, J=7.3Hz, 2H); LCMS (ESI): m/z 256/258 [M+H⁺]; Rt=1.93 min; method A.

Intermediate 10: ethyl3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate

To a stirred solution of3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoic acid (for exampleas prepared for Intermediate 9) (400 mg, 1.56 mmol) in ethanol (20 mL)was added conc. sulphuric acid (2-3 drops) and heated at reflux for 4 h.After completion of the reaction, the reaction mixture was concentratedunder reduced pressure. The obtained residue was neutralized withsaturated sodium hydrogen carbonate solution and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure toafford ethyl 3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate (435mg, 98%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.66 (s, 1H), 7.05 (s, 1H), 4.17 (q, J=7.1Hz, 2H), 3.99 (s, 3H), 3.23 (t, J=7.9 Hz, 2H), 2.88 (t, J=7.9 Hz, 2H),1.26 (t, J=7.1 Hz, 3H); LCMS (ESI): m/z 284/286 [M+H⁺]; Rt=2.43 min;method A.

Intermediate 10a (Intermediate 10 alternative preparation): ethyl3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate

To a stirred solution of3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoic acid (for exampleas prepared for Intermediate 9a) (160 g, 627.4 mmol) in ethanol (1.6 L)was added conc. sulphuric acid (160 mL) drop-wise at 10° C. The reactionmixture was heated at reflux for 4 h. After completion of the reaction,the mixture was concentrated under reduced pressure. The obtainedresidue was neutralized with saturated sodium hydrogen carbonatesolution. The solid precipitate was isolated by filtration and washedwith petroleum ether to afford ethyl3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate (150 g, 84%) as abrown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (s, 1H), 7.49 (s, 1H), 4.06 (q, J=7.1Hz, 2H), 3.96 (s, 3H), 3.19 (t, J=7.3 Hz, 2H), 2.84 (t, J=7.3 Hz, 2H),1.15 (t, J=7.1 Hz, 3H); LCMS (ESI): m/z 284/286 [M+H⁺]; Rt=2.41 min;method A.

Intermediate 11: ethyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate

To a stirred solution of ethyl3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate (for example asprepared for Intermediate 10) (415 mg, 1.46 mmol) in DCM (20 mL) wasadded anhydrous aluminium chloride (975 mg, 7.33 mmol) portion-wise at0° C. The reaction mixture was heated to reflux temperature andmaintained for 16 h. After completion of the reaction, the reactionmixture was diluted with water (20 mL). The organic layer was separated,washed with brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The crude product was purified by silica gel(100-200 mesh) column chromatography using 20% ethyl acetate in hexaneas eluent to afford ethyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (338 mg, 86%) asan off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 11.12 (s, 1H), 7.97 (s, 1H), 7.12 (s, 1H),4.06 (q, J=7.1 Hz, 2H), 3.16 (t, J=7.3 Hz, 2H), 2.82 (t, J=7.3 Hz, 2H),1.15 (t, J=7.1 Hz, 3H); LCMS (ESI): m/z 270/272 [M+H⁺]; Rt=2.14 min;method A.

Intermediate 11a (Intermediate 11 alternative preparation): ethyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate

To a stirred solution of ethyl3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate (for example asprepared for Intermediate 10a) (150 g, 528.7 mmol) in DCM (2.5 L) wasadded aluminium chloride (351.5 g, 2643 mmol) portion-wise at 0° C. Thereaction mixture was heated at reflux for 16 h. After completion of thereaction, the mixture was diluted with water. The organic layer wasseparated, washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude solid was washed withpetroleum ether to afford ethyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (90 g, 63%) as abrown solid.

¹H NMR (400 MHz, DMSO-d₆): δ 11.11 (s, 1H; D₂O exchangeable), 7.97 (s,1H), 7.12 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.16 (t, J=7.3 Hz, 2H), 2.82(t, J=7.3 Hz, 2H), 1.15 (t, J=7.1 Hz, 3H); LCMS (ESI): m/z 270/272 [M⁺];Rt=2.40 min; method A.

Intermediate 12: (S)-1-(pyridin-2-yl)ethyl methanesulfonate

To a stirred solution of (S)-1-(pyridin-2-yl)ethanol (150 mg, 1.21 mmol)in DCM (10 mL) was added triethylamine (0.25 mL, 1.82 mmol) and mesylchloride (0.11 mL, 1.46 mmol) at 0° C. The reaction was stirred at 0° C.for 30 min. After completion of the reaction, the reaction mixture wasdiluted with water and the organic layer was separated. The organicphase was dried over anhydrous sodium sulfate and evaporated underreduced pressure to afford (S)-1-(pyridin-2-yl)ethyl methanesulfonate(215 mg) as a thick liquid, which was directly taken for next reactionwithout purification.

Intermediate 12a (Intermediate 12 Alternative Preparation):(S)-1-(pyridin-2-yl)ethyl methanesulfonate

To a stirred solution of (S)-1-(pyridin-2-yl)ethanol (35 g, 284.2 mmol)in DCM (700 mL) were added triethylamine (42.79 g, 423.6 mmol) and mesylchloride (36.2 g, 317.8 mmol) at 0° C. The reaction was stirred at RTfor 2 h. After completion of the reaction, the reaction solution waswashed with brineand the organic phase evaporated under reduced pressureto afford (S)-1-(pyridin-2-yl)ethyl methanesulfonate (57 g, 99%) as apink liquid, which was directly taken for the next reaction withoutpurification.

Intermediate 13: (R)-ethyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate

To a stirred solution of ethyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (for example asprepared for Intermediate 11) (150 mg, 0.55 mmol) in DMF (6 mL) wereadded potassium carbonate (115 mg, 0.83 mmol) and a solution of(S)-1-(pyridin-2-yl)ethyl methanesulfonate (for example as prepared forIntermediate 12) (168 mg, 0.83 mmol) in DMF (6 mL) at RT. The reactionmixture was heated at 60° C. for 12 h. After completion of the reaction,the reaction mixture was diluted with water and extracted with ethylacetate (2×25 mL). The combined organic extracts were washed with brine,dried over anhydrous sodium sulfate and evaporated under reducedpressure to afford the crude. The crude product was purified by silicagel (100-200 mesh) column chromatography using 20% ethyl acetate inhexane as eluent to afford (R)-ethyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate(180 mg, 86%) as an oil.

¹H NMR (400 MHz, DMSO-d₆): δ 8.59 (m, 1H), 8.08 (s, 1H), 7.83 (td,J=7.7, 1.8 Hz, 1H), 7.51 (dt, J=7.7, 1.1 Hz, 1H), 7.38 (s, 1H), 7.33(ddd, J=7.7, 4.8, 1.1 Hz, 1H), 5.77 (q, J=6.3 Hz, 1H), 4.06 (q, J=7.1Hz, 2H), 3.16 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.68 (d, J=6.3Hz, 3H), 1.15 (t, J=7.1 Hz, 3H); LCMS (ESI): m/z 375/377 [M+H⁺]; Rt=2.50min; method A.

Intermediate 13a (Intermediate 13 Alternative Preparation): (R)-ethyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate

To a stirred solution of ethyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (for example asprepared for Intermediate 11a) (48 g, 177.9 mmol) in DMF (800 mL) wereadded potassium carbonate (61 g, 442 mmol) and (S)-1-(pyridin-2-yl)ethylmethanesulfonate (for example as prepared for Intermediate 12a) (57 g,283.5 mmol) at 0-10° C. The reaction mixture was heated at 75-80° C. for16 h. After completion of the reaction, the reaction mixture was dilutedwith saturated ammonium chloride solution and extracted with ethylacetate. The combined organic extracts were evaporated under reducedpressure. The crude product was purified by silica gel (100-200 mesh)column chromatography eluting with 13% ethyl acetate in petroleum etherto afford (R)-ethyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate(54 g, 81%) as a pale yellow semi-solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (m, 1H), 8.08 (s, 1H), 7.82 (td,J=7.7, 1.8 Hz, 1H), 7.51 (dt, J=7.9, 1.1 Hz, 1H), 7.37 (s, 1H), 7.32(ddd, J=7.7, 4.9, 1.1 Hz, 1H), 5.76 (q, J=6.4 Hz, 1H), 4.04 (q, J=7.1Hz, 2H), 3.16 (t, J=7.3 Hz, 2H), 2.81 (t, J=7.3 Hz, 2H), 1.68 (d, J=6.4Hz, 3H), 1.14 (t, J=7.1 Hz, 3H); LCMS (ESI): m/z 375/377 [M+H⁺]; Rt=2.51min; method A.

Intermediate 14: ethyl2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetate

To a stirred solution of2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetic acid (for example asprepared for Intermediate 4a) (60 g, 248.3 mmol) in ethanol (750 mL) wasadded conc. sulphuric acid (60 mL) drop-wise at 10° C. The reactionmixture was heated to reflux and maintained for 2 h. After completeconsumption of the starting material, the reaction was concentratedunder reduced pressure. The residue was neutralized with saturatedaqueous sodium hydrogen carbonate solution and extracted with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford ethyl2-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)acetate (60 g, 90%) as abrown solid.

¹H NMR (400 MHz, CDCl₃): δ 7.69 (s, 1H), 7.05 (s, 1H), 4.21 (q, J=7.1Hz, 2H), 3.97 (s, 3H), 3.94 (s, 2H), 1.26 (t, J=7.1 Hz, 3H); LCMS (ESI):m/z 270/272 [M+H⁺]; Rt=2.37 min; method A.

Intermediate 15: 1-Chloro-2,4-dimethoxybenzene

To 4-chlororesorcinol (100 g, 691.8 mmol) in acetone (1000 mL), wasadded potassium carbonate (286.4 g, 2075.3 mmol) and the reactionmixture stirred at room temperature for 30 min. Dimethyl sulphate (500mL) was added; the mixture was heated to 60° C. and stirred for 16 h.The mixture was filtered and the filtrate concentrated to afford1-chloro-2,4-dimethoxybenzene as a yellow oil (124 g, crude).

¹H NMR (300 MHz, CDCl₃) δ 7.23 (s, 1H), 6.51 (d, J=2.7 Hz, 1H), 6.43(dd, J=8.7, 2.7 Hz, 1H), 3.88 (s, 3H), 3.80 (s, 3H)].

Intermediate 16: 4-(5-Chloro-2,4-dimethoxyphenyl)-4-oxobutanoic acid

To 1-chloro-2,4-dimethoxybenzene (for example as prepared forIntermediate 15, 124 g, 691.8 mmol) in DCM (1000 mL), was added succinicanhydride (76.2 g, 760.98 mmol) at 0° C. Aluminium chloride (120 g,899.34 mmol) was added also at 0° C., the reaction mixture was warmed toroom temperature and stirred for 30 min. The mixture was poured intoice-water (1000 mL), filtered and dried to afford4-(5-chloro-2,4-dimethoxyphenyl)-4-oxobutanoic acid as a white solid(127 g).

LCMS (Method I): Rt=1.40 min, [M+H]⁺ 273.

Intermediate 17: Methyl 4-(5-chloro-2,4-dimethoxyphenyl)-4-oxobutanoate

To 4-(5-chloro-2,4-dimethoxyphenyl)-4-oxobutanoic acid (for example asprepared for Intermediate 16, 127 g, 465.7 mmol) in MeOH (500 mL), wasadded thionyl chloride (66.5 g, 558.8 mmol) at 0° C. The reactionmixture was warmed to room temperature and stirred for 16 h. The solventwas removed, water (500 mL) was to the residue and the mixture extractedwith DCM (500 mL×3). The combined organic phases were dried over sodiumsulphate and purified by silica gel column chromatography [silica,200-300 mesh, 1000 g, eluted with petroleum ether/ethyl acetate 4:1 toDCM/MeOH 100:1] to afford methyl4-(5-chloro-2,4-dimethoxyphenyl)-4-oxobutanoate as a pink solid (120.4g).

LCMS (Method I): Rt=1.54 min, [M+H]⁺ 287.

Intermediate 18: Methyl4-(5-chloro-2-hydroxy-4-methoxyphenyl)-4-oxobutanoate

To methyl 4-(5-chloro-2,4-dimethoxyphenyl)-4-oxobutanoate (for exampleas prepared for Intermediate 17, 120.4 g, 420 mmol) in MeCN (800 mL),was added sodium iodide (93.9 g, 630 mmol) and aluminium chloride (56 g,420 mmol). After the addition the mixture was poured into ice-water(1000 mL) and extracted with ethyl acetate (600 mL×4). The combinedorganic phases were concentrated and purified with silica gel columnchromatography [silica, 200-300 mesh, 500 g, eluted with petroleumether/ethyl acetate 5:1 to DCM/MeOH 100:1] to afford methyl4-(5-chloro-2-hydroxy-4-methoxyphenyl)-4-oxobutanoate as a yellow solid(95.3 g).

LCMS (Method I): Rt=1.57 min, [M+H]⁺ 273.

Intermediate 19: Methyl4-(5-chloro-2-hydroxy-4-methoxyphenyl)-4-(hydroxyimino)butanoate

To methyl 4-(5-chloro-2-hydroxy-4-methoxyphenyl)-4-oxobutanoate (forexample as prepared for Intermediate 18, 95.3 g, 272.68 mmol) inpyridine/MeOH (1:1, 500 mL), was added hydroxylamine hydrochloride (72.6g, 1044.6 mmol) and the reaction mixture was stirred at 100° C. for 16h. The solvent was removed, water (500 mL) was added to the residue andthe mixture extracted with DCM (500 mL×3). The solvent was removed fromthe combined organic phases and the residue purified with silica gelcolumn chromatography [silica, 200-300 mesh, 500 g, eluted with DCM:MeOH 100:1] to afford methyl4-(5-chloro-2-hydroxy-4-methoxyphenyl)-4-(hydroxyimino)butanoate as ayellow solid (50 g).

LCMS (Method I): Rt=1.48 min, [M+H]⁺ 288.

Intermediate 20: Methyl3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate

Methyl 4-(5-chloro-2-hydroxy-4-methoxyphenyl)-4-(hydroxyimino)butanoate(for example as prepared for Intermediate 19, 53.4 g, 185.6 mmol) wasadded to pyridine/acetic anhydride (1:1, 500 mL) and the reactionmixture was stirred at 110° C. for 16 h, and then at 120° C. for 16 h.The solvent was removed and the residue was purified with silica gelcolumn chromatography [silica, 200-300 mesh, 500 g, eluted withpetroleum ether/ethyl acetate 5:1 to DCM/MeOH 100:1] to afford 2 batchesof methyl 3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate (purplesolid, 20 g) and (white solid, 9 g).

LCMS (Method I): Rt=1.53 min, [M+H]⁺ 270 for both batches.

Intermediate 21: Methyl3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate

To methyl 3-(5-chloro-6-methoxybenzo[d]isoxazol-3-yl)propanoate (forexample as prepared for Intermediate 20, 29 g, 107.53 mmol) in DCM (500mL), was added aluminium chloride (72 g, 537.7 mmol) at room temperatureand the reaction mixture was stirred at room temperature for 16 h. Themixture was poured into ice/water (500 mL), extracted with DCM (400mL×3) and dried over sodium sulphate. The solvent was removed and theresidue purified with silica gel column chromatography [silica, 200-300mesh, 200 g, eluted with DCM/petroleum ether 1:1 to DCM/ethyl acetate100:3] to afford 3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoateas a yellow solid (22 g).

LCMS (Method I): Rt=1.39 min, [M+H]⁺ 256.

Intermediate 22: (R)-Methyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate

To methyl 3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (forexample as prepared for Intermediate 21, 21.5 g, 84.1 mmol) in THF (300mL), was added (S)-1-(pyridin-2-yl)ethanol (10.3 g, 84.1 mmol),triphenylphosphine (26.5 g, 100.92 mmol), diethyl azodicarboxylate (17.6g, 100.92 mmol), and the reaction mixture was stirred at roomtemperature for 16 h. The solvent was removed and the residue purifiedby silica gel column chromatography [silica: 200-300 mesh, 300 g, elutedwith petroleum ether/ethyl acetate 7:1] to afford (R)-methyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoateas a pale yellow oil (28 g).

LCMS (Method I): Rt=1.61 min, [M+H]⁺ 361.

Intermediate 23: 6-Methyl-2-tosyl-2,3-dihydropyridazine-3-carbonitrile

A solution of 3-methylpyridazine (47 g, 500 mmol) in DCM (500 mL), wasadded trimethylsilyl cyanide (90 g, 900 mmol) and aluminium chloride(0.4 g) and the mixture stirred at room temperature for 30 min.p-Toluenesulfonyl chloride (163.8 g, 900 mmol) in DCM was addeddrop-wise at room temperature and the reaction mixture stirred at roomtemperature for 16 h. The solvent was evaporated and the residual solidwashed with ethanol (300 mL) to afford6-methyl-2-tosyl-2,3-dihydropyridazine-3-carbonitrile as a white solid(115 g).

¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.0 Hz,2H), 6.23 (dd, J=9.2, 6.7 Hz, 1H), 6.14-6.06 (m, 1H), 5.70 (d, J=6.7 Hz,1H), 2.46 (s, 3H), 2.15 (s, 3H).

Intermediate 23a (Intermediate 23 Alternative Preparation):6-methyl-2-tosyl-2,3-dihydropyridazine-3-carbonitrile

To a solution of 3-methylpyridazine (289 g, 3.07 mol) in DCM (4 L), wasadded trimethylsilyl cyanide (368 g, 3.68 mol) and aluminium chloride(2.5 g, 18.8 mmol) and the reaction mixture was stirred at roomtemperature for 30 min. p-Toluenesulfonyl chloride (670 g, 3.68 mol) wasadded in portions at room temperature and the reaction stirred at roomtemperature for 3 h. The solvent was evaporated and the solid was washedwith ethanol (2 L) to give6-methyl-2-tosyl-2,3-dihydropyridazine-3-carbonitrile as a white solid(688 g).

¹H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.1 Hz,2H), 6.23 (dd, J=9.2, 6.7 Hz, 1H), 6.10 (d, J=9.2 Hz, 1H), 5.70 (d,J=6.7 Hz, 1H), 2.46 (s, 3H), 2.14 (s, 3H); LCMS(A): Rt=1.47 min, MH⁺276.

Intermediate 24: 6-Methylpyridazine-3-carbonitrile

A solution of 6-methyl-2-tosyl-2,3-dihydropyridazine-3-carbonitrile (forexample as prepared for Intermediate 23 115 g, 0.41 mol) in THF (1 L),was added 1,8-diazabicyclo[5.4.0]undec-7-ene (75 g, 0.49 mol) drop-wiseat room temperature. The reaction mixture was stirred at roomtemperature for 2 h, the solvent evaporated and DCM (2 L) was added. Themixture was washed with water (1 L), dried and concentrated. The residuewas purified with column chromatography [silica, 200-300 mesh, 500 g,eluted with petroleum ether/ethyl acetate 1:2] to afford6-methylpyridazine-3-carbonitrile as a yellow solid (37.6 g).

LCMS (Method I): Rt=0.93 min, [M+H]⁺ 120.

Intermediate 24a (Intermediate 24 Alternative Preparation):6-methylpyridazine-3-carbonitrile

To a solution of 6-methyl-2-tosyl-2,3-dihydropyridazine-3-carbonitrile(688 g, 2.5 mol) in THF (3 L, anhydrous) was added dropwise1,8-diazabicyclo[5.4.0]undec-7-ene (400 g, 2.63 mol) at room temperatureand the reaction mixture was stirred at room temperature for 2 h. Thesolvent was evaporated and DCM (3 L) was addedto the residue. Themixture was washed with water (2 L), dried with magnesium sulfate andthe solvent evaporated. The residue was purified with columnchromatography (silica, 2 Kg, eluted with petroleum ether/ethyl acetate1:1) to give 6-methylpyridazine-3-carbonitrile as a yellow solid (228g).

¹H NMR (300 MHz, CDCl₃) δ 7.74 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.6 Hz,1H), 2.86 (s, 3H); LCMS(Method I): Rt=1.01 min, MH⁺ 120.

Intermediate 25: 1-(6-Methylpyridazin-3-yl)ethanone

To a solution of 6-methylpyridazine-3-carbonitrile (for example asprepared for Intermediate 24, 28 g, 250 mmol) in toluene (300 mL) anddiethyl ether (300 mL), was added methyl magnesium bromide (3M in ether,208 ml, 625 mmol) drop-wise at −10° C. The reaction mixture was stirredat 0° C. for 2 h. Hydrochloric acid (2N, 400 mL) was added and stirredat 0° C. for 15 min., then the aqueous phase was basified with sodiumbicarbonate. The mixture was extracted with DCM (500 mL×3), dried andevaporated. The residue was purified by flash chromatography [silica,200-300 mesh, 500 g, eluted with petroleum ether/ethyl acetate 2:1] toafford 1-(6-methylpyridazin-3-yl)ethanone as a brown solid (20 g).

LCMS (Method I): Rt=1.08 min, [M+H]⁺ 137.

Intermediate 25a (Intermediate 25 Alternative Preparation):1-(6-methylpyridazin-3-yl)ethanone

To a solution of 6-methylpyridazine-3-carbonitrile (228 g, 1.92 mol) intoluene (2 L, anhydrous) and diethyl ether (2 L, anhydrous) was addedmethyl magnesium bromide (3M in ether, 0.77 L, 2.3 mol) dropwise at −10°C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h andquenched by addition of hydrochloric acid (2N, 2 L). The aqueous phasewas separated and adjusted to pH 7-8 with sodium bicarbonate (solid).The aqueous phase was extracted with DCM (2 L×3), dried with magnesiumsulfate and evaporated. The residue was purified by columnchromatography (silica: 100-200 mesh, 2 Kg, eluted with petroleumether/ethyl acetate 1:1) to afford 1-(6-methylpyridazin-3-yl)ethanone asa brown solid (151 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.6 Hz,1H), 2.87 (s, 3H), 2.81 (s, 3H); LCMS (Method I): Rt=1.11 min, MH⁺ 137.

A portion of this material (70 g, 515 mmol) was dissolved inhydrochloric acid (2 N, 500 mL), the reaction mixture was stirred atroom temperature for 2 h, then adjusted to pH 8 with sodium bicarbonate(solid). The mixture was extracted with DCM (500 mL×3), dried withmagnesium sulfate and the solvent evaporated to give1-(6-methylpyridazin-3-yl)ethanone as a brown solid (68 g).

¹H NMR (300 MHz, CDCl₃) δ 8.00 (d, J=8.6 Hz, 1H), 7.47 (d, J=8.6 Hz,1H), 2.87 (s, 3H), 2.80 (s, 3H); LCMS (Method I): Rt=1.11 min, MH⁺ 137.

Intermediate 26: (S)-1-(6-Methylpyridazin-3-yl)ethanol

To a solution of(R)-3,3-diphenyl-1-methylpyrrolidino[1,2-c]-1,3,2-oxazaborole (R-CBS, 1Min toluene, 10 mL, 10 mmol) in THF (50 mL) was added borane-methylsulfide complex (2M, 5 mL, 10 mmol) and the reaction mixture was stirredat room temperature for 1 h. 1-(6-methylpyridazin-3-yl)ethanone (forexample as prepared for Intermediate 25, 1.36 g, 10 mmol) was added andthe reaction mixture was stirred at room temperature for 4 h undernitrogen. MeOH was added, the solvent was evaporated and the residue waspurified by flash chromatography [silica: 200-300 mesh, 40 g, elutedwith petroleum ether/ethyl acetate 1:1 to DCM/MeOH 10:1] to afford(S)-1-(6-methylpyridazin-3-yl)ethanol (330 mg).

LCMS (Method I): Rt=0.55 min, [M+H]⁺ 139.

Intermediate 26a (Intermediate 26 Alternative Preparation):(S)-1-(6-methylpyridazin-3-yl)ethanol

To a solution of 1-(6-methylpyridazin-3-yl)ethanone (58.7 g, 431 mmol)and RuCl₂[(R)-xylbinap][(R)-daipen] (CAS no 220114-32-9, 1.05 g, 0.862mmol) in isopropanol (800 mL) was added potassium tert-butoxide (10.5 g,86.2 mol) and the reaction mixture was stirred at room temperature underhydrogen atmosphere (50 psi) for 72 h. The volatiles were evaporated andthe residue purified by column chromatography [silica: 100-200 mesh, 1Kg, eluted with DCM/MeOH 20:1] to give(S)-1-(6-methylpyridazin-3-yl)ethanol as a brown solid (17 g).

¹H NMR (300 MHz, CDCl₃) δ 7.46 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.6 Hz,1H), 5.11 (q, J=6.5 Hz, 1H), 4.11 (s, 1H), 2.72 (s, 3H), 1.57 (d, J=6.6Hz, 3H); LCMS (Method I): Rt=0.50 min, MH⁺ 139.

Intermediate 27: 1-(6-Methylpyridazin-3-yl)ethanol

To a solution of 1-(6-methylpyridazin-3-yl)ethanone (for example asprepared for Intermediate 25, 10 g, 73.5 mmol) in MeOH (50 mL), wasadded sodium borohydride (5.58 g, 147 mmol) at room temperature and thereaction mixture stirred at room temperature for 2 h. The solvent wasevaporated and DCM was added. The mixture was filtered and the residuewashed with DCM. The combined organic phases were evaporated and theresidue purified with flash chromatography [silica, 200-300 mesh, 80 g,eluted with DCM/MeOH 20:1] to afford 1-(6-methylpyridazin-3-yl)ethanolas an oil (8.2 g). LCMS (Method I): Rt=0.55 min, [M+H]⁺ 139.

Intermediate 28: 1-(6-Methylpyridazin-3-yl)ethyl methanesulfonate

To a solution of 1-(6-methylpyridazin-3-yl)ethanol (for example asprepared for Intermediate 27, 8.2 g, 59.4 mmol) in DCM (100 mL), wasadded triethylamine (7.2 g, 71.3 mmol) and methanesulfonyl chloride(8.55 g, 59.4 mmol) and the reaction mixture stirred at room temperaturefor 2 h. The reaction was quenched with water (50 mL), extracted withDCM (50 mL×3) and the combined organic phased dried and the solventevaporated. The residue was purified by flash chromatography [silica;200-300 mesh, 80 g, eluted with DCM/MeOH 20:1] to afford1-(6-methylpyridazin-3-yl)ethyl methanesulfonate as a brown oil (9.8 g).

LCMS (Method I): Rt=1.16 min, [M+H]⁺ 217.

Intermediate 29: Methyl3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate

To methyl 3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate (forexample as prepared for Intermediate 21, 7.67 g, 30 mmol) and1-(6-methylpyridazin-3-yl)ethyl methanesulfonate (for example asprepared for Intermediate 28, 30 mmol) in MeOH (500 mL) was addedpotassium carbonate (8.28 g, 60 mmol) and the reaction mixture wasstirred at 70° C. for 16 h. The solvent was evaporated and the residuepurified by silica gel column chromatography [silica, 200-300 mesh, 150g, eluted with DCM/ethyl acetate 10:1] to obtain methyl3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoateas a white solid (8.5 g).

LCMS (Method I): Rt=1.48 min, [M+H]⁺ 376.

Intermediate 30: (R)-methyl3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate

To a solution of (S)-1-(6-methylpyridazin-3-yl)ethanol (20.7 g, 150mmol) and methyl 3-(5-chloro-6-hydroxybenzo[d]isoxazol-3-yl)propanoate(38.2 g, 150 mmol) in THF (200 mL, anhydrous) and toluene (200 mL,anhydrous) was added diethyl azodicarboxylate (31.3 g, 180 mmol) andtriphenylphosphine (47.2 g, 180 mmol). The reaction mixture was stirredat room temperature for 3 hours, the volatiles evaporated and theresidue purified by column chromatography (silica: 100-200 mesh, 1.5 Kg,eluted with DCM/ethyl acetate 5:1) to give (R)-methyl3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoateas an off-white solid (49.5 g).

¹H NMR (300 MHz, CDCl₃) δ 7.65 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.35 (d,J=8.6 Hz, 1H), 7.06 (s, 1H), 5.86 (d, J=6.4 Hz, 1H), 3.71 (s, 3H), 3.20(t, J=7.3 Hz, 2H), 2.88 (t, J=7.4 Hz, 2H), 2.74 (s, 3H), 1.84 (d, J=6.5Hz, 3H); LCMS (Method I): Rt=1.43 min, MH⁺ 376.

EXAMPLES Example 1:(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid

To a stirred solution of (R)-ethyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate(for example as prepared for Intermediate 13) (180 mg, 0.48 mmol) inTHF:ethanol:water (5:2:2; 9 mL) was added lithium hydroxide hydrate (40mg, 0.96 mmol) and maintained at RT for 2 h. After completion of thereaction, the reaction was concentrated under reduced pressure andacidified to pH-4 with citric acid. The resultant solution was extractedwith ethyl acetate. The combined organic extracts were washed withbrine, dried over anhydrous sodium sulphate and evaporated under reducedpressure to afford solid, which was triturated with petroleum ether(2×10 mL) to afford(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid (75 mg, 45%) as semi-solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.24 (s, 1H; D₂O exchangeable), 8.58 (dd,J=4.9, 1.7 Hz, 1H), 8.07 (s, 1H), 7.82 (td, J=7.8, 1.7 Hz, 1H), 7.51 (d,J=7.8 Hz, 1H), 7.39 (s, 1H), 7.33 (dd, J=7.8, 4.9 Hz, 1H), 5.76 (q,J=6.4 Hz, 1H), 3.12 (t, J=7.3 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H), 1.68 (d,J=6.4 Hz, 3H); LCMS (ESI): m/z 347/349[M+H⁺]; Rt=1.05 min; method B.

Example 1a (Example 1 alternative preparation):(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid

To a stirred solution of (R)-ethyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate(for example as prepared for Intermediate 13a) (53 g, 141.6 mmol) inTHF:water (1:1; 1 L) was added lithium hydroxide monohydrate (23.77 g,566.6 mmol) at 0-10° C. and allowed to stir at RT for 2 h. Aftercompletion of the reaction, the mixture was concentrated under reducedpressure and diluted with water. The resultant solution was washed withdiethyl ether and acidified up to pH-2. The resultant solution wasextracted with DCM. The combined organic extracts were dried overanhydrous sodium sulphate and evaporated under reduced pressure. Thecrude material was triturated with n-pentane to afford(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid (48 g, 96%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (s, 1H; D₂O exchangeable), 8.58 (dd,J=4.9, 1.8 Hz, 1H), 8.07 (s, 1H), 7.82 (td, J=7.8, 1.8 Hz, 1H), 7.51 (d,J=7.8 Hz, 1H), 7.37 (s, 1H), 7.33 (dd, J=7.8, 4.9 Hz, 1H), 5.77 (q,J=6.4 Hz, 1H), 3.13 (t, J=7.3 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 1.68 (d,J=6.4 Hz, 3H); LCMS (ESI): m/z 345/347 [M−H]⁻; Rt=2.04 min; method A;Chiral HPLC: 96.2% ee; method G.

The obtained solid was purified by chiral preparative SFC to afford99.99% enantiomerically pure(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid (35 g) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 12.25 (s, 1H; D₂O exchangeable), 8.58 (dd,J=4.9, 1.8 Hz, 1H), 8.07 (s, 1H), 7.82 (td, J=7.8, 1.8 Hz, 1H), 7.51 (d,J=7.8 Hz, 1H), 7.37 (s, 1H), 7.33 (dd, J=7.8, 4.9 Hz, 1H), 5.77 (q,J=6.4 Hz, 1H), 3.13 (t, J=7.3 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 1.68 (d,J=6.4 Hz, 3H); LCMS (ESI): m/z 347.1 [M+H⁺]; 99.6%; Rt=3.33 min; methodE; Chiral HPLC: 99.99% ee; method G.

Preparative Chiral SFC Conditions:

Column/dimensions: CHIRALPAK-IA (250 mm×30 mm); eluent: CO₂=50.0%; %methanol=50.0%; total flow: 90 g/min; back pressure: 100 bar; UV: 235nm; stack time: 38.0 min; instrument: Thar SFC 200.

Analytical Chiral SFC Conditions:

Column/dimensions: CHIRALPAK-IA (250 mm×4.6 mm); eluent: CO₂=60.0%; %methanol=40.0%; total flow: 4 g/min; back pressure: 100 bar; UV: 292 nm;stack time: 1.82 min.

Example 1b:(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic acid, tris(hydroxymethyl)aminomethane)

A solution of(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid (for example as prepared for Example 1) (70 mg, 0.20 mmol) andtris(hydroxymethyl)aminomethane (24 mg, 0.20 mmol) in methanol (10 mL)was heated at 60° C. for 2 h. After 2 h, the reaction mixture wasconcentrated under reduced pressure to afford a semi-solid, which wasthen triturated with diethyl ether (10 mL) to afford(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoic acid, tris(hydroxymethyl)aminomethane) salt (72 mg, 76%) as anoff-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (dd, J=4.8, 1.8 Hz, 1H), 8.06 (s, 1H),7.82 (td, J=7.8, 1.8 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.36 (s, 1H), 7.32(dd, J=7.8, 4.8 Hz, 1H), 5.76 (q, J=6.4 Hz, 1H), 4.68 (bs, 6H; D₂Oexchangeable), 3.27 (s, 6H), 3.10 (t, J=7.3 Hz, 2H), 2.64 (t, J=7.3 Hz,2H), 1.68 (d, J=6.4 Hz, 3H); LCMS (ESI): m/z 347/349 [M+H⁺]; Rt=1.99min; method A.

Examples 1c-1 m were prepared in a manner analogous to the preparationof Example 1 b.

Examples 2-28 were prepared in a manner analogous to Examples 1 or 1a.

Re- Molecu- tention Example lar ion + Time LCMS no. Name StructureIdentity (min) Method 1c (R)-3-(5-chloro-6- (1-(pyridin-2-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid compound with sulfuricacid (1:1)

347 [M + H⁺] 2.04 A 1d sodium (R)-3-(5- chloro-6-(1- (pyridin-2-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoate

347 [M + H⁺] 2.03 A 1e (R)-3-(5-chloro-6- (1-(pyridin-2-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid compound with(S)-2-amino-5- guanidinopentanoic acid (1:1)

347[M + H⁺] 2.02 A 1f (R)-3-(5-chloro-6- (1-(pyridin-2-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid compound with (S)-2,6-diaminohexanoic acid (1:1)

347 [M + H⁺] 2.03 A 1g (R)-3-(5-chloro-6- (1-(pyridin-2-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid hydrochloride

347 [M + H⁺] 2.01 A 1h (2R,3R,4R,5S)-6- (methylamino) hexane-1,2,3,4,5-pentanol (R)-3-(5- chloro-6-(1- (pyridin-2- yl)ethoxy)benzo[d]isoxazol-3- yl)propanoate

347 [M + H⁺] 2.02 A 1i (R)-3-(5-chloro-6- (1-(pyridin-2-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid compound withmethanesulfonic acid (1:1)

347 [M + H⁺] 2.06 A 1j N-benzyl-2- phenylethanamine (R)-3-(5-chloro-6-(1-(pyridin-2- yl)ethoxy)benzo[d] isoxazol-3- yl)propanoate

347 [M + H⁺] 7.64* F 1k N¹,N²- dibenzylethane- 1,2-diamine (R)-3-(5-chloro-6-(1- (pyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (1:2)

347 [M + H⁺] 7.65* F 1l N¹-(2- aminoethyl)ethane- 1,2-diamine(R)-3-(5-chloro-6- (1-(pyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (1:3)

347 [M + H⁺] 2.03 A 1m (R)-3-(5-chloro-6- (1-(pyridin-2-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid compound with 4-methylbenzene- sulfonic acid (1:1)

347 [M + H⁺] 7.72* F 2 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6- (pyridin-2- ylmethoxy)benzo [d]isoxazol-3- yl)propanoate

333 [M + H⁺] 1.90 A 3 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1-(5- methylpyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

361 [M + H⁺] 2.10 A 4 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1-(5- methylpyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

361 [M + H⁺] 2.10 A 5 3-(5-chloro-6-(1- (pyridin-2- yl)ethoxy)benzo[d]isoxazol-3- yl)propanoic acid (racemic)

347 [M + H⁺] 2.83 D 6 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-((5- fluoropyridin-2- yl)methoxy)benzo [d]isoxazol-3-yl)propanoate

351 [M + H⁺] 2.17 A 7 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-((5- chloropyridin-2- yl)methoxy)benzo [d]isoxazol-3-yl)propanoate

367[M + H⁺] 2.32 A 8 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-((5- methylpyridin-2- yl)methoxy)benzo [d]isoxazol-3-yl)propanoate

347 [M + H⁺] 1.91 A 9 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1- (oxazol-2- yl)ethoxy)benzo[d] isoxazol-3- yl)propanoate(single unidentified enantiomer)

337 [M + H⁺] 1.94 A 10 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1- (oxazol-2- yl)ethoxy)benzo[d] isoxazol-3- yl)propanoate(single unidentified enantiomer)

337 [M + H⁺] 1.94 A 11 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1-(5- fluoropyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

365 [M + H⁺] 2.09 A 12 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1-(5- fluoropyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

365 [M + H⁺] 2.09 A 13 3-(5-chloro-6- (pyridazin-3- ylmethoxy)benzo[d]isoxazol-3- yl)propanoic acid

334 [M + H⁺] 1.66 A 14 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1- (pyrimidin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

348 [M + H⁺] 1.86 A 15 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1- (pyrimidin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

348 [M + H⁺] 1.86 A 16 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1-(5- chloropyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

381 [M + H]⁺ 2.41 A 17 3-(5-chloro-6-((6- methylpyridazin- 3-yl)methoxy)benzo [d]isoxazol-3- yl)propanoic acid

348 [M + H]⁺ 1.74 A 18 2-amino-2- (hydroxymethyl) propane-1,3-diol 3-(5-chloro-6-(1-(5- chloropyridin-2- yl)ethoxy)benzo[d] isoxazol-3-yl)propanoate (single unidentified enantiomer)

381 [M + H]⁺ 2.41 A 19 (S)-3-(5-chloro-6- (1-(6- methylpyridazin- 3-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid

362 [M + H]⁺ 1.84 A 20 (R)-3-(5-chloro-6- (1-(6- methylpyridazin- 3-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid

362 [M + H]⁺ 1.85 A 21 3-(5-chloro-6-(1- (pyridazin-3-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

348 [M + H]⁺ 1.80 A 22 3-(5-chloro-6-(1- (pyridazin-3-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

348 [M + H]⁺ 1.80 A 23 3-(5-chloro-6-(1- (5-methylpyridin- 2-yl)propoxy)benzo [d]isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

375 [M + H]⁺ 2.30 A 24 3-(5-chloro-6-(1- (5-methylpyridin- 2-yl)propoxy)benzo [d]isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

375 [M + H]⁺ 2.29 A 25 3-(5-chloro-6-(1- (pyridin-2- yl)propoxy)benzo[d]isoxazol-3- yl)propanoic acid (single unidentified enantiomer)

361 [M + H]⁺ 2.19 A 26 3-(5-chloro-6-(1- (pyridin-2- yl)propoxy)benzo[d]isoxazol-3- yl)propanoic acid (single unidentified enantiomer)

361 [M + H]⁺ 2.19 A 27 3-(5-chloro-6-(1- (5-chloropyridin- 2-yl)propoxy)benzo [d]isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

395 [M + H]⁺ 2.56 A₅ 28 3-(5-chloro-6-(1- (5-chloropyridin- 2-yl)propoxy)benzo [d]isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

395 [M + H]⁺ 2.53 10 A 15

Also prepared were(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid 2-aminoethanol salt,(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid 1,2-ethanedisulphonic acid salt and bis((R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid) sulphate.

Example 1n (Example 1 Alternative Preparation):(R)-3-(5-Chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid

To (R)-methyl3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate(for example as prepared for Intermediate 22, 28 g, 77.6 mmol) in THF(500 mL), was added lithium hydroxide (1N, 310 mL, 310 mmol) and themixture was stirred at room temperature for 1 h. The organic sovent wasremoved, hydrochloric acid (1N) was added until the mixture reached pH 6and the mixture then extracted with ethyl acetate (300 mL×3). Thecombined organic phases were dried over sodium sulphate andconcentrated. The residue was dissolved in THF (50 mL), hexane (300 mL)was added and the resulting solid isolated by filteration and dried toafford(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid as a white solid (22.7 g).

LCMS (Method I): Rt=1.46 min, [M+H]⁺ 347.

¹H NMR (300 MHz, CD₃OD) δ 8.55 (ddd, J=4.9, 1.7, 0.9 Hz, 1H), 7.87 (s,1H), 7.83 (td, J=7.8, 1.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.34 (ddd,J=7.6, 4.9, 1.2 Hz, 1H), 7.07 (s, 1H), 5.62 (q, J=6.4 Hz, 1H), 3.19 (t,J=7.3 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 1.76 (d, J=6.5 Hz, 3H); HPLC: 214nm 100%, 254 nm 100%, chiral-HPLC: 214 nm 97.5%, 254 nm 98.4%.

Example 20a (Example 20 Alternative Preparation):(R)-3-(5-Chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid

To a solution of methyl3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate(for example as prepared for Intermediate 29, 8.5 g, 22.7 mmol) in THF(100 mL), was added lithium hydroxide (3N, 30 mL, 90.8 mmol) and thesolution stirred at room temperature for 2 h. The solvent wasevaporated, water (50 mL) was added and the pH adjusted to between pH2-3 with hydrochloric acid (1 N). The solid was isolated by filtrationand dried in air to give a white solid. This solid was purified bychiral-prep-HPLC [SFC, column:chiralpak-IC,CO₂-MeOH (formic acid)] toobtain(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid as an off-white solid (3.57 g).

LCMS (Method I): Rt=1.37 min, [M+H]⁺ 362. ¹H NMR (300 MHz, d₆-DMSO) δ12.29 (s, 1H), 8.08 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.60 (d, J=8.8 Hz,1H), 7.48 (s, 1H), 6.03 (dd, J=12.7, 6.3 Hz, 1H), 3.12 (t, J=7.2 Hz,2H), 2.73 (t, J=7.2 Hz, 2H), 2.60 (s, 3H), 1.73 (d, J=6.4 Hz, 3H). HPLC:214 nm 98.9%, 254 nm 99.5%.

Example 20b (Example 20 Alternative Preparation):(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid

To(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid (79.5 g, 220 mmol, ee 89.5%) in MeCN (2 L), L(+)-arginine (38.3 g,220 mmol) was added and the reaction mixture was stirred at 55° C. for0.5 h. The mixture was cooled to room temperature, the solid wasfiltered and washed with MeCN (200 mL) and dried in air to give a whitesolid. The solid was added to hydrochloric acid (37%, 1.5 L), andstirred at room temperature for 1 h, filtered and the solid washed withwater (500 mL×3) and dried in air to give(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicas a white solid, (68 g, ee 100%).

¹H NMR (400 MHz, d₆-DMSO) δ 12.29 (s, 1H), 8.09 (s, 1H), 7.70 (d, J=8.7Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.49 (s, 1H), 6.04 (q, J=6.4 Hz, 1H),3.13 (t, J=7.3 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.61 (s, 3H), 1.74 (d,J=6.4 Hz, 3H); LCMS (Method I): Rt=1.36 min, MH⁺ 362.

Example 20c (Example 20 Alternative Preparation):(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid

To a solution of (R)-methyl3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoate(87 g, 231.5 mmol) in THF (500 mL) was added lithium hydroxide (2N inwater, 462 mL), the reaction mixture was stirred at room temperature for4 hours, the organic solvent was evaporated and the residual aqueousphase washed with ethyl acetate (500 mL×3). The aqueous phase wasacidified with hydrochloric acid (2N) to pH=2-3, the solid was isolatedby filtration and washed with water (300 mL×3). The solid was air driedto give(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicas a light-yellow solid (76 g, 92%, ee 89.5%).

¹H NMR (300 MHz, d₆-DMSO) δ 12.28 (s, 1H), 8.08 (s, 1H), 7.70 (d, J=8.7Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.48 (s, 1H), 6.03 (q, J=6.3 Hz, 1H),3.13 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.2 Hz, 2H), 2.61 (s, 3H), 1.74 (d,J=6.4 Hz, 3H); LCMS(Method I): Rt=1.40 min, MH⁺ 362.

Re- Molecu- tention Example lar ion + Time Meth- no. Name StructureIdentity (min) od 29 3-{5-Chloro-6-[1- (5-ethylpyridin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

375 [M + H]⁺ 2.30 A 30 3-{5-Chloro-6-[1- (5-ethylpyridin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

375 [M + H]⁺ 2.30 A 31 3-{5-Chloro-6-[1- (6-ethylpyridin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

375 [M + H]⁺ 2.26 A 32 3-{5-Chloro-6-[1- (6-ethylpyridin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

375 [M + H]⁺ 2.27 A 33 3-{5-Chloro-6-[(5- chloropyrimidin-2-yl)methoxy]-1,2- benzoxazol-3- yl}propanoic acid

368 [M + H]⁺ 1.44 I 34 3-{5-Chloro-6-[(5- methylpyrimidin-2-yl)methoxy]- 1,2-benzoxazol-3- yl}propanoic acid

348 [M + H]⁺ 1.358 I 35 3-{5-Chloro-6-[1- (2-methyl-1,3- oxazol-5-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

351 [M + H]⁺ 1.94 A 36 3-{5-Chloro-6-[1- (2-methyl-1,3- oxazol-5-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

351 [M + H]⁺ 1.96 A 37 3-{5-Chloro-6-[1- (5- chloropyrimidin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

383 [M + H]⁺ 1.519 I 38 3-{5-Chloro-6-[1- (5- chloropyrimidin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

383 [M + H]⁺ 1.511 I 39 3-{5-Chloro-6-[1- (5- methylpyrimidin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

362 [M + H]⁺ 1.44 I 40 3-{5-Chloro-6-[1- (5- methylpyrimidin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

362 [M + H]⁺ 1.44 I 41 3-{5-Chloro-6-[1- (4-ethyl-1,3- oxazol-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

365 [M + H]⁺ 2.21 A 42 3-{5-Chloro-6-[1- (4-ethyl-1,3- oxazol-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

365 [M + H]⁺ 2.20 A 43 3-{5-Chloro-6- [(1S)-1- (pyrimidin-2-yl)propoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

362 [M + H]⁺ 2.03 A 44 3-{5-Chloro-6-[1- (pyrimidin-2- yl)propoxy]-1,2-benzoxazol-3- yl}propanoic acid (single unidentified enantiomer)

362 [M + H]⁺ 2.03 A 45 3-{5-Chloro-6-[1- (pyridazin-3- yl)propoxy]-1,2-benzoxazol-3- yl}propanoic acid (single unidentified enantiomer)

362 [M + H]⁺ 1.90 A 46 3-{5-Chloro-6-[1- (pyridazin-3- yl)propoxy]-1,2-benzoxazol-3- yl}propanoic acid (single unidentified enantiomer)

362 [M + H]⁺ 1.90 A 47 3-{5-Chloro-6-[1- (6- methylpyridazin-3-yl)propoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

376 [M + H]⁺ 1.94 A 48 3-{5-Chloro-6-[1- (6- methylpyridazin-3-yl)propoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

376 [M + H]⁺ 1.94 A 49 3-{5-Chloro-6-[1- (5- methylpyrimidin-2-yl)propoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

376 [M + H]⁺ 2.11 A 50 3-{5-Chloro-6-[1- (5- methylpyrimidin-2-yl)propoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

376 [M + H]⁺ 2.11 A 51 3-{5-Chloro-6-[1- (5- chloropyrimidin-2-yl)propoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

396 [M + H]⁺ 2.34 A 52 3-{5-Chloro-6-[1- (5- chloropyrimidin-2-yl)propoxy]-1,2- benzoxazol-3- yl}propanoic acid (single unidentifiedenantiomer)

396 [M + H]⁺ 2.34 A 53 3-(5-chloro-6-(1- (1-ethyl-1H- pyrazol-3-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

364/ 366 [M + H]⁺ 2.02 A 54 3-(5-chloro-6-(1- (1-ethyl-1H- pyrazol-3-yl)ethoxy)benzo[d] isoxazol-3- yl)propanoic acid (single unidentifiedenantiomer)

364/ 366 [M + H]⁺ 2.02 A 55 3-{5-chloro-6- [(1R)-1-(3- fluoropyridin-2-yl)ethoxy]-1,2- benzoxazol-3- yl}propanoic acid

365/ 367 [M + H⁺] 1.50 I

Methods of Use

Certain compounds of the invention are inhibitors of KMO. Compoundswhich inhibit KMO may be useful in the treatment of various conditionsor disorders mediated by KMO, for example acute pancreatitis, chronickidney disease, acute kidney disease, acute kidney injury, otherconditions associated with systemic inflammatory response syndrome(SIRS), Huntington's disease, Alzheimer's disease, spinocerebellarataxias, Parkinson's disease, AIDS-dementia complex, HIV infection,amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis,cardiovascular shock, severe trauma, acute lung injury, acuterespiratory distress syndrome, acute cholecystitis, severe burns,pneumonia, extensive surgical procedures, ischemic bowel, severe acutehepatic disease, severe acute hepatic encephalopathy or acute renalfailure.

Additional conditions or disorders include hyperproliferative diseasesof benign or malignant behaviour, in which cells of various tissues andorgans exhibit aberrant patterns of growth, proliferation, migration,signalling, senescence, and death. Generally hyperproliferative diseaserefers to diseases and disorders associated with the uncontrolledproliferation of cells, including but not limited to uncontrolled growthof organ and tissue cells resulting in cancers and benign tumours.Hyperproliferative disorders associated with endothelial cells canresult in diseases of angiogenesis such as angiomas, endometriosis,obesity, age-related macular degeneration and various retinopathies, aswell as the proliferation of ECs and smooth muscle cells that causerestenosis as a consequence of stenting in the treatment ofatherosclerosis. Hyperproliferative disorders involving fibroblasts(i.e. fibrogenesis) include but are not limited to disorders ofexcessive scaring (i.e. fibrosis) such as age-related maculardegeneration, cardiac remodelling and failure associated with myocardialinfarction, excessive wound healing such as commonly occurs as aconsequence of surgery or injury, keloids, and fibroid tumours andstenting.

Further such conditions or disorders include transplant rejection(suppression of T-cells) and graft vs host disease, systemicinflammatory disorders, brain inflammatory disorders including malariaand African trypanosomiasis, and pneumococcal meningitis.

Further such conditions or disorders include cirrhosis, chronicpancreatitis, liver fibrosis, lung fibrosis and ischemia-reperfusioninjury.

Further such conditions or disorders include, for example,neurodegenerative diseases, psychiatric or neurological diseases ordisorders, Creutzfeld-Jacob disease, trauma-induced neurodegeneration,high-pressure neurological syndrome, dystonia, olivopontocerebellaratrophy, multiple sclerosis, epilepsy, consequences of stroke, cerebralischemia, ischemic disorders including stroke (focal ischemia), hypoxia,multi-infarct dementia, consequences of cerebral trauma or damage,damage to the spinal cord, dementia such as senile dementia,AIDS-induced encephalopathy, other infection related encephalopathy,viral or bacterial meningitis, infectious diseases caused by viral,bacterial and other parasites, (for example, general central nervoussystem (CNS) infections such as viral, bacterial or parasitic infection,for example, poliomyelitis, Lyme disease (Borrelia burgdorferiinfection)) septic shock, and cancers, cancers with cerebrallocalization, hepatic encephalopathy, systemic lupus, analgesia andopiate withdrawal symptoms, feeding behaviour, psychiatric disorders,such as insomnia, severe deficit in working memory, severe deficit inlong term memory storage, decrease in cognition, severe deficit inattention, severe deficit in executive functioning, slowness ininformation processing, slowness in neural activity, anxiety,generalized anxiety disorders, panic anxiety, obsessive compulsivedisorders, social phobia, performance anxiety, post-traumatic stressdisorder, acute stress reaction, adjustment reaction, separation anxietydisorder, alcohol withdrawal anxiety, depressive disorders, disorders ofthe developing or aged brain, diabetes, and complications thereof,Tourette's syndrome, Fragile X syndrome, autism spectrum disorders,disorders that cause severe and pervasive impairment in thinkingfeeling, language and the ability to relate to others, mood disorders,psychological disorders characterized by abnormalities of emotionalstate, such as without limitation, bipolar disorder, unipolardepression, major depression, endogenous depression, involutionaldepression, reactive depression, psychotic depression, depression causedby underlying medical conditions, cyclothymic disorders, dysthymicdisorders, mood disorders due to general medical condition, mooddisorders not otherwise specified and substance-induced mood disorders.

Further such conditions or disorders also include, for example, acutenecrotizing pancreatitis, AIDS (disease), aseptic meningitis, braindisease, for example, Gilles de la Tourette syndrome, Asperger syndrome,Rett syndrome, pervasive developmental disorders, aging-related braindisease, and developmental brain disease, burnout syndrome, carbonmonoxide poisoning, cardiac arrest or insufficiency and hemorrhagicshock (global brain ischemia), cataract formation and aging of the eye,central nervous system disease, cerebrovascular disease, chronic fatiguesyndrome, chronic stress, cognitive disorders, convulsive disorders,such as variants of grand mal and petit mal epilepsy and Partial ComplexEpilepsy, diabetes mellitus, disease of the nervous system (e.g.,dyskinesia, L-DOPA induced movement disorders, drug addiction, pain andcataract), drug dependence, drug withdrawal, feeding disorders, GuillainBarr Syndrome and other neuropathies, immune disease, immunitarydisorders and therapeutic treatment aimed at modifying biologicalresponses (for instance administrations of interferons or interleukins),inflammatory disorders of the central and/or peripheral nervous system,Injury (trauma, polytrauma), Mental and behavioral disorders, metabolicdisease, pain disease, or disorder selected from a group of inflammatorypain, neurophathic pain or migraine, allodynia, hyperalgesia pain,phantom pain, neuropathic pain related to diabetic neuropathy, multipleorgan failure, near drowning, necrosis, neoplasms of the brain,neoplastic disorders including lymphomas and other malignant blooddisorders, nervous system disease (high-pressure neurological Syndrome,infection), nicotine addiction and other addictive disorders includingalcoholism, cannabis, benzodiazepine, barbiturate, morphine and cocainedependence, change in appetite, sleep disorders, changes in sleeppattern, lack of energy, fatigue, low self-esteem, self-reproachinappropriate guilt, frequent thoughts of death or suicide, plans orattemps to commit suicide, feelings of hopelessness and worthlessness,psychomotor agitation or retardation, diminished capacity for thinking,concentration, or decisiveness, as a neuroprotective agent, spinal corddisease, systemic lupus erythematosis, traumatic damage to the brain andspinal cord, and tremor syndromes and poor balance, brakykinesia,rigidity, tremor, change in speech, loss of facial expression,micrographia, difficulty swallowing, drooling, confusion, fear, sexualdysfunction, language impairment, impairment in decision making, violentoutbursts, aggression, hallucination, apathy, impairment in abstractthinking.

Further such conditions or disorders also include, for example,cardiovascular diseases, which refer to diseases and disorders of theheart and circulatory system. These diseases are often associated withdyslipoproteinemias and/or dyslipidemias. Cardiovascular diseasesinclude, but are not limited to, cardiomegaly, atherosclerosis,myocardial infarction, and congestive heart failure, coronary heartdisease, hypertension and hypotension.

In particular, such conditions or disorders include conditions ordisorders where elevated levels of tryptophan metabolites have beencorrelated with severity of disease and poor prognosis, including shock,trauma in patients with multiple organ failure, severe acutepancreatitis and chronic kidney disease (Logters, T. T., et al. (2009)Shock 32: 29-34, Dabrowski et al (2014) Inflammation 37: 223-234,Changsirivathanathamrong et al (2011) Critical Care Medicine 39:2678-2683, Mole, D. J., et al. (2008) Br J Surg 95: 855-867, Zhao (2013)Renal Failure 35: 648-653, Pawlak, K. et al (2009) Blood Coagulation andFibrinolysis 20: 590-594, Kabayashi, T. et al (2014) Biochemical andBiophysical Research Communications 445: 412-416).

The methods of treatment of the invention comprise administering atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, to a patient in need thereof.Individual embodiments of the invention include methods of treating anyone of the above-mentioned disorders by administering a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, to a patient in need thereof.

As used herein, ‘treat’ or ‘treatment’ in reference to a disorder means:(1) to ameliorate or prevent the disorder or one or more of thebiological manifestations of the disorder, (2) to interfere with (a):one or more points in the biological cascade that leads to or isresponsible for the disorder, or (b): one or more of the biologicalmanifestations of the disorder, (3) to alleviate one or more of thesymptoms or effects associated with the disorder, or (4) to slow theprogression of the disorder or one or more of the biologicalmanifestations of the disorder.

As indicated above, ‘treatment’ of a disorder may include prevention orprophylaxis of the disorder. It will be appreciated that ‘prevention’ isnot an absolute term. In medicine, ‘prevention’ is understood to referto the prophylactic administration of a drug to substantially diminishthe likelihood or severity of a disorder or biological manifestationthereof, or to delay the onset of such disorder or biologicalmanifestation thereof.

As used herein, ‘effective amount’ in reference to a compound of formula(I), or a pharmaceutically acceptable salt thereof, or otherpharmaceutically-active agent means an amount of the compound sufficientto treat the patient's condition within the scope of sound medicaljudgment. An effective amount of a compound will vary with theparticular compound chosen (for example, the potency, efficacy, andhalf-life of the compound will be considered); the route ofadministration chosen; the disorder being treated; the severity of thedisorder being treated; the age, size, weight, and physical condition ofthe patient being treated; the medical history of the patient to betreated; the duration of the treatment; the nature of concurrenttherapy; the desired therapeutic effect; and like factors, but cannevertheless be routinely determined by the skilled artisan.

As used herein “patient” refers to a human (including adults andchildren) or other mammal. In one embodiment, “patient” refers to ahuman.

The invention further provides, in a further aspect, a method oftreatment of a condition or disorder mediated by KMO (such as theaforementioned disorders), which method comprises administering to apatient in need thereof a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of acutepancreatitis, chronic kidney disease, acute kidney disease, acute kidneyinjury, other conditions associated with systemic inflammatory responsesyndrome (SIRS), Huntington's disease, Alzheimer's disease,spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, HIVinfection, amylotrophic lateral sclerosis (ALS), depression,schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lunginjury, acute respiratory distress syndrome, acute cholecystitis, severeburns, pneumonia, extensive surgical procedures, ischemic bowel, severeacute hepatic disease, severe acute hepatic encephalopathy or acuterenal failure which method comprises administering to a patient in needthereof a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of acutepancreatitis, chronic kidney disease, other conditions associated withsystemic inflammatory response syndrome (SIRS), Huntington's disease,Alzheimer's disease, spinocerebellar ataxias, Parkinson's disease,AIDS-dementia complex, amylotrophic lateral sclerosis (ALS), depression,schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lunginjury, acute respiratory distress syndrome, acute cholecystitis, severeburns, pneumonia, extensive surgical procedures, ischemic bowel, severeacute hepatic disease, severe acute hepatic encephalopathy or acuterenal failure which method comprises administering to a patient in needthereof a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of acutepancreatitis, which method comprises administering to a patient in needthereof a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of acutepancreatitis, which method comprises administering to a patient in needthereof a therapeutically effective amount of(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of acutepancreatitis, which method comprises administering to a patient in needthereof a therapeutically effective amount of(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of chronickidney disease, which method comprises administering to a patient inneed thereof a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of chronickidney disease, which method comprises administering to a patient inneed thereof a therapeutically effective amount of(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided a method of treatment of chronickidney disease, which method comprises administering to a patient inneed thereof a therapeutically effective amount of(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

In a further aspect, there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in therapy.

In one embodiment, there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment of acondition or disorder mediated via KMO.

In one embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofacute pancreatitis, chronic kidney disease, acute kidney disease, acutekidney injury, other conditions associated with systemic inflammatoryresponse syndrome (SIRS), Huntington's disease, Alzheimer's disease,spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex, HIVinfection, amylotrophic lateral sclerosis (ALS), depression,schizophrenia, sepsis, cardiovascular shock, severe trauma, acute lunginjury, acute respiratory distress syndrome, acute cholecystitis, severeburns, pneumonia, extensive surgical procedures, ischemic bowel, severeacute hepatic disease, severe acute hepatic encephalopathy or acuterenal failure.

In one embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofacute pancreatitis, chronic kidney disease, other conditions associatedwith systemic inflammatory response syndrome (SIRS), Huntington'sdisease, Alzheimer's disease, spinocerebellar ataxias, Parkinson'sdisease, AIDS-dementia complex, amylotrophic lateral sclerosis (ALS),depression, schizophrenia, sepsis, cardiovascular shock, severe trauma,acute lung injury, acute respiratory distress syndrome, acutecholecystitis, severe burns, pneumonia, extensive surgical procedures,ischemic bowel, severe acute hepatic disease, severe acute hepaticencephalopathy or acute renal failure.

In one embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofacute pancreatitis.

In one embodiment there is provided(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof. for use in thetreatment of acute pancreatitis.

In one embodiment there is provided(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof. for use in thetreatment of acute pancreatitis.

In one embodiment there is provided a compound of formula (I) or apharmaceutically acceptable salt thereof for use in the treatment ofchronic kidney disease.

In one embodiment there is provided(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof. for use in thetreatment of chronic kidney disease.

In one embodiment there is provided(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof. for use in thetreatment of chronic kidney disease.

In a further aspect, there is provided the use of a compound of formula(I) or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for the treatment of a condition or disorder mediated viaKMO.

In one embodiment there is provided the use of a compound of formula (I)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the treatment of acute pancreatitis, chronickidney disease, acute kidney disease, acute kidney injury, otherconditions associated with systemic inflammatory response syndrome(SIRS), Huntington's disease, Alzheimer's disease, spinocerebellarataxias, Parkinson's disease, AIDS-dementia complex, HIV infection,amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis,cardiovascular shock, severe trauma, acute lung injury, acuterespiratory distress syndrome, acute cholecystitis, severe burns,pneumonia, extensive surgical procedures, ischemic bowel, severe acutehepatic disease, severe acute hepatic encephalopathy or acute renalfailure.

In one embodiment there is provided the use of a compound of formula (I)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the treatment of acute pancreatitis, chronickidney disease, other conditions associated with systemic inflammatoryresponse syndrome (SIRS), Huntington's disease, Alzheimer's disease,spinocerebellar ataxias, Parkinson's disease, AIDS-dementia complex,amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis,cardiovascular shock, severe trauma, acute lung injury, acuterespiratory distress syndrome, acute cholecystitis, severe burns,pneumonia, extensive surgical procedures, ischemic bowel, severe acutehepatic disease, severe acute hepatic encephalopathy or acute renalfailure.

In one embodiment there is provided the use of a compound of formula (I)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the treatment of acute pancreatitis.

In one embodiment there is provided the use of(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for use in the treatment of acute pancreatitis.

In one embodiment there is provided the use of(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for use in the treatment of acute pancreatitis.

In one embodiment there is provided the use of a compound of formula (I)or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the treatment of chronic kidney disease.

In one embodiment there is provided the use of(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for use in the treatment of chronic kidney disease.

In one embodiment there is provided the use of(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for use in the treatment of chronic kidney disease.

A particular compound of the invention for use in the aforementionedmethods of treatment is(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

A particular compound of the invention for use in the aforementionedmethods of treatment is(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid or a pharmaceutically acceptable salt thereof.

Compositions

The compounds of the invention will normally, but not necessarily, beformulated into pharmaceutical compositions prior to administration to apatient. Accordingly, in another aspect, there is provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients. The pharmaceutical compositionof the invention, which may be prepared by admixture, suitably atambient temperature and atmospheric pressure, is usually adapted fororal, parenteral or rectal administration and, as such, may be in theform of tablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable or infusible solutions orsuspensions or suppositories.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting of the compound or compoundsof formula (I) or pharmaceutically acceptable salts thereof onceadministered to the patient from one organ, or portion of the body, toanother organ, or portion of the body. Certain pharmaceuticallyacceptable excipients may be chosen for their ability to enhance patientcompliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: Diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweetners, flavouring agents, flavour-masking agents, colouring agents,anti-caking agents, humectants, chelating agents, plasticisers,viscosity increasing agents, antioxidants, preservatives, stabilisers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what other excipientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

The pharmaceutical composition of the invention, which may be preparedby admixture, suitably at ambient temperature and atmospheric pressure,is usually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories.

The pharmaceutical composition of the invention may contain from 0.1% to99% by weight of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned conditions or disorders will vary in the usual way withthe seriousness of the conditions or disorders, the weight of thesubject, and other similar factors. However, as a general guide suitableunit doses may be 0.05 to 5000 mg, 1.0 to 500 mg or 1.0 to 200 mg andsuch unit doses may be administered once a day or more than once a day,for example two or three times a day. Such therapy may extend for anumber of weeks, months or years.

In one embodiment injectable or infusible solutions, or reconstitutablepowders, are preferred.

In one embodiment, a composition adapted for oral formulation ispreferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); tabletting lubricants (e.g. magnesiumstearate, talc or silica); disintegrants (e.g. potato starch or sodiumstarch glycollate); and acceptable wetting agents (e.g. sodium laurylsulphate). The tablets may be coated according to methods well known innormal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. Formulations for injection may bepresented in unit dosage form e.g. in ampoules or in multi-dose,utilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle, optionally with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. The compound, depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle. In preparingsolutions, the compound can be dissolved for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are dissolved in the vehicle. To enhance the stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parenteral suspensions are prepared insubstantially the same manner, except that the compound is suspended inthe vehicle instead of being dissolved, and sterilisation cannot beaccomplished by filtration. The compound can be sterilised by exposureto ethylene oxide before suspension in a sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device. Thuscompounds of the invention may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

The invention provides for a pharmaceutical composition for use in thetreatment of acute pancreatitis, chronic kidney disease, acute kidneydisease, acute kidney injury, other conditions associated with systemicinflammatory response syndrome (SIRS), Huntington's disease, Alzheimer'sdisease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementiacomplex, HIV infection, amylotrophic lateral sclerosis (ALS),depression, schizophrenia, sepsis, cardiovascular shock, severe trauma,acute lung injury, acute respiratory distress syndrome, acutecholecystitis, severe burns, pneumonia, extensive surgical procedures,ischemic bowel, severe acute hepatic disease, severe acute hepaticencephalopathy or acute renal failure which comprises a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient.

The invention provides for a pharmaceutical composition for use in thetreatment of acute pancreatitis, chronic kidney disease, otherconditions associated with systemic inflammatory response syndrome(SIRS), Huntington's disease, Alzheimer's disease, spinocerebellarataxias, Parkinson's disease, AIDS-dementia complex, amylotrophiclateral sclerosis (ALS), depression, schizophrenia, sepsis,cardiovascular shock, severe trauma, acute lung injury, acuterespiratory distress syndrome, acute cholecystitis, severe burns,pneumonia, extensive surgical procedures, ischemic bowel, severe acutehepatic disease, severe acute hepatic encephalopathy or acute renalfailure which comprises a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptableexcipients.

Biological Data

KMO inhibition can be determined by MS Rapidfire assay performed on thehuman cloned enzyme as described herein. The compounds of the Exampleshave demonstrated inhibitory activity at the KMO enzyme, using the MSRapidfire functional assay described herein, or a substantially similarassay.

KMO MS Rapidfire Assay Protocol

Materials and Methods

Materials

L-Kynurenine (Kyn), 3-hydroxy-DL-kynurenine (3-HK), β-Nicotinamideadenine dinucleotide 2′-phosphate reduced tetrasodium salt hydrate(NADPH), 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (Hepes),DL-dithiothreitol (DTT), ethylenediaminetetraacetic acid (EDTA), CHAPSand trifluoroacetic acid (TFA) were purchased from Sigma-Aldrich Ltd.(Gillingham, Dorset, UK). HPLC-grade acetonitrile and formic acid weresupplied by Fisher Scientific (Loughborough, UK).

Cloning and Expression of Human KMO

Full length human KMO was amplified by PCR frompcDNA5/FRT/V5-His-TOPO/hKMO (vector supplied by the University ofEdinburgh) and cloned into pGEX6P-1 (GE Healthcare) using BamH1 and Sallrestriction sites. DNA encoding the N-terminal glutathione-S-transferase(GST) tag, followed by a Pre-Scission protease cleavage site, and thefull length KMO was amplified by PCR from pGEX6P-1-KMO and cloned intopFastbacl (Invitrogen) using Xbal and EcoR1 restriction sites.

pFastbacl GST-KMO was transposed into the baculovirus genome using theBAC-to-BAC technology (Invitrogen) and bacmid DNA was prepared andtransfected into Spodoptera frugiperda (Sf9) cells using Cellfectin II(Invitrogen). Expression of a protein of the expected molecular weight(Mr 82,634) was seen by Western blot analysis using anti-GST-peroxidaseconjugate.

Preparation of Membranes from Sf9 Cells Expressing Human GST-KMO

A P1 virus stock was generated from a single clone and used to infect 3×1.5 L cultures of Sf9 cells in 3 L Corning Fernbach flasks. The Sf9cells were grown in Hyclone SFX media (Thermo Scientific) to about 3×10⁶cells/ml and were infected at a nominal multiplicity of infection of 3.Cells were harvested after 48 hours and disrupted by blending in 50 mMHepes, pH 7.4, 1 mM EDTA buffer containing protease inhibitors. A lowspeed spin (400 g) was used to remove cell debris, followed by a highspeed spin (75 000 g) to pellet the membranes. The membranes werepurified in a discontinuous sucrose density gradient by re-suspending in10% (w/v) sucrose and layering over 40% (w/v) sucrose, both in the abovebuffer. This was centrifuged at 150 000 g and the purified membraneswere taken from the interface, collected by centrifugation at 100 000 g,resuspended in buffer and aliquoted for storage at −80° C. KMO activitywas found to be associated with the membrane fraction only and no KMOactivity was detected in membranes prepared from uninfected Sf9 cells. Abatch of 104 mg of purified Sf9 KMO-membranes (as determined by thePierce BCA protein assay using bovine serum albumin as standard) wasprepared and validated in the RapidFire High-Throughput MassSpectrometry (RF MS) assay.

RapidFire High-Throughput Mass Spectrometry Assay

Method 1

11 point, 3-fold serial dilutions of test compounds were prepared inDMSO and 100 nL of these solutions were dispensed into 384-well V-basepolypropylene plates (Greiner Bio-one, Stonehouse, UK) using an Echo 555acoustic dispenser (Labcyte, Sunnyvale, Calif.). This gave a final assayconcentration range between 100 μM and 1.7 nM in 10 μL final assayvolume (see below). 100 nL DMSO was dispensed into columns 6 and 18 forhigh and low controls, respectively, with prior inactivation of theenzyme in column 18 by pre-dispense of 30 μL of 0.5% (v/v) TFA.

Conditions for the assay of human KMO using isolated KMO-membranes were50 mM Hepes, pH 7.5, 2 mM DTT, 1 mM EDTA, 100 μM CHAPS, 200 μM NADPH, 10μM Kynurenine and 8 μg/ml KMO-membranes in a total reaction volume of 10μL.

Assays were performed by initially dispensing 5 μL of a 2× Enzymesolution (16 μg/ml KMO-membranes in 50 mM Hepes, pH 7.5, 2 mM DTT, 2 mMEDTA, 200 μM CHAPS) into plates containing 100 nL compounds andincubating for 10 min at ambient temperature. Reactions were initiatedby addition of 5 μL of 2× Substrate solution (400 μM NADPH, 20 μMKynurenine in 50 mM Hepes, pH 7.5, 2 mM DTT) and incubated for 2 h atroom temperature before quenching the reaction with 30 μL of 0.5% (v/v)TFA. Plates were centrifuged at 2500 rpm for 10 min before analysis. Alladditions were made using a Multidrop Combi dispenser (Thermo FisherScientific).

Quenched assay plates were transferred to a high-throughput RapidFire200integrated autosampler/solid-phase extraction (SPE) system (AgilentTechnologies, Wakefield, Mass.).

Samples were aspirated from each well for 500 ms and 10 μL was loadeddirectly onto a RapidFire micro-scale SPE C18 (type C) cartridge, whichwas washed for 3 s with HPLC-grade water containing 0.1% (v/v) formicacid to remove non-organic components. Analytes were then eluted intothe mass spectrometer, in a 3 s elution cycle, using 80% (v/v)acetonitrile/water containing 0.1% (v/v) formic acid, and the cartridgewas then equilibrated by washing with water containing 0.1% (v/v) formicacid for 500 ms. This gave a total cycle time of 7 s, enabling analysisof a 384-well plate in approximately 45 min.

Both Kyn and 3-HK were detected using a Sciex API4000 triple quadrupolemass spectrometer (Applied Biosystems, Concord, Ontario, Canada),equipped with an electrospray interface and operated in positive ionmode. Multiple reaction monitoring (MRM) was used to detect both Kyn and3-HK using Q1/Q3 transitions at m/z 209.4 to 192.0 and m/z 225.3 to208.2, respectively. The mass spectrometer used an ESI voltage of 5500 Vand a source temperature of 600° C., with a dwell time of 50 ms for eachtransition.

Data Analysis

Individual MRM transitions were saved as text files and the extractedion chromatograms were integrated and processed using the RapidFire®peak integration software (version 3.6).

Using the integrated peak area for 3-HK data was analysed withinActivityBase (ID Business Solutions Ltd, Surrey, UK). Dose responsecurves were fitted to equation (1):

$\begin{matrix}{{{Inhibition}\mspace{14mu} (\%)} = {\frac{\left( {a - d} \right)}{1 + \left( \frac{\lbrack I\rbrack}{{IC}_{50}} \right)^{S}} + d}} & (1)\end{matrix}$

Where a is the uninhibited response, d is the fully inhibited response,[I] is the inhibitor concentration, IC₅₀ is [I] that gives 0.5×(a-d) andS is the Hill slope.

Method 2

11 point, 3-fold serial dilutions of test compounds were prepared inDMSO and 100 nL of these solutions were dispensed into 384-well V-basepolypropylene plates (Greiner Bio-one, Stonehouse, UK) using an Echo 555acoustic dispenser (Labcyte, Sunnyvale, Calif.). This gave a final assayconcentration range between 10 μM and 0.17 nM in 10 μL final assayvolume (see below). 100 nL DMSO was dispensed into columns 6 and 18 forhigh and low controls, respectively, with prior inactivation of theenzyme in column 18 by pre-dispense of 50 μL of 0.5% (v/v) TFA.

Conditions for the assay of human KMO using isolated KMO-membranes were50 mM Hepes, pH 7.5, 2 mM DTT, 1 mM EDTA, 100 μM CHAPS, 200 μM NADPH, 10μM Kynurenine and 4 μg/ml KMO-membranes in a total reaction volume of 10μL.

Assays were performed by initially dispensing 5 μL of a 2× Enzymesolution (8 μg/ml KMO-membranes in 50 mM Hepes, pH 7.5, 2 mM DTT, 2 mMEDTA, 200 μM CHAPS) into plates containing 100 nL compounds andincubating for 30 min at ambient temperature. Reactions were initiatedby addition of 5 μL of 2× Substrate solution (400 μM NADPH, 20 μMKynurenine in 50 mM Hepes, pH 7.5, 2 mM DTT) and incubated for 2 h atroom temperature before quenching the reaction with 50 μL of 0.5% (v/v)TFA. Plates were centrifuged at 3000 rpm for 10 min before analysis. Alladditions were made using a Multidrop Combi dispenser (Thermo FisherScientific).

Quenched assay plates were transferred to a high-throughput RapidFire200integrated autosampler/solid-phase extraction (SPE) system (AgilentTechnologies, Wakefield, Mass.). Samples were aspirated from each wellfor 650 ms and approximately 10 μL was loaded directly onto a RapidFiremicro-scale SPE C18 (type C) cartridge, which was washed for 1500 mswith HPLC-grade water containing 0.1% (v/v) formic acid to removenon-organic components. Analytes were then eluted into the massspectrometer, in a 1500 ms elution cycle, using 80% (v/v)acetonitrile/water containing 0.1% (v/v) formic acid, and the cartridgewas then equilibrated by washing with water containing 0.1% (v/v) formicacid for 500 ms. This gave a total cycle time of 7 s, enabling analysisof a 384-well plate in approximately 45 min.

Both Kyn and 3-HK were detected using a Sciex API4000 triple quadrupolemass spectrometer (Sciex, Warrington, Cheshire, UK), equipped with anelectrospray interface and operated in positive ion mode. Multiplereaction monitoring (MRM) was used to detect both Kyn and 3-HK usingQ1/Q3 transitions at m/z 209.2 to 192.0 and m/z 225.2 to 208.1,respectively. The mass spectrometer used an ESI voltage of 5500 V and asource temperature of 650° C., with a dwell time of 50 ms for eachtransition.

Data Analysis

Individual MRM transitions were saved as text files and the extractedion chromatograms were integrated and processed using the RapidFire®peak integration software (version 4.0).

Using the integrated peak area for 3-HK data was analysed withinActivityBase (ID Business Solutions Ltd, Surrey, UK). Dose responsecurves were fitted to equation (1):

$\begin{matrix}{{{Inhibition}\mspace{14mu} (\%)} = {\frac{\left( {a - d} \right)}{1 + \left( \frac{\lbrack I\rbrack}{{IC}_{50}} \right)^{S}} + d}} & (1)\end{matrix}$

Where a is the uninhibited response, d is the fully inhibited response,[I] is the inhibitor concentration, IC₅₀ is [I] that gives 0.5×(a-d) andS is the Hill slope.

The compounds of Examples 1-54 were tested essentially as described inat least one of the above assays. Those of skill in the art willrecognise that in vitro binding assays and cell-based assays forfunctional activity are subject to experimental variability.Accordingly, it is to be understood that the pIC₅₀ values given beloware exemplary only.

Exemplified compounds of the invention have median pIC₅₀ values of ≧5.0in at least one of the above MS Rapidfire assays.

Certain exemplified compounds of the invention have median pIC₅₀ valuesof ≧5.5 in at least one of the above MS Rapidfire assays.

Examples 1, 1a-1 m, 2, 3, 5-9, 13, 15-17, 20, 22, 23, 25 and 27 havemedian pIC₅₀ values of ≧8.0 in at least one of the above MS Rapidfireassays. Examples 29, 31, 35, 37, 39, 41, 43, 46, 47, 49 and 51 havemedian pIC₅₀ values of 8.0 in at least one of the above MS Rapidfireassays.

Example 1b has a median pIC₅₀=8.6 in at least one of the above MSRapidfire assays. Examples 3 and 7 have a median pIC₅₀ value in at leastone of the above MS Rapidfire assays of 8.6. Example 20 has a medianpIC₅₀ value in at least one of the above MS Rapidfire assays of 8.7.Example 25 has a median pIC₅₀ value in at least one of the above MSRapidfire assays of 8.4.

Examples 20a and 20b have median pIC₅₀ values at least one of the aboveMS Rapidfire assays of 8.7.

What is claimed is:
 1. A compound of formula (I)

wherein: R¹ is heteroaryl either unsubstituted or substituted by methyl,ethyl, halo or ═O; and R² is H, methyl or ethyl. or a salt thereof.
 2. Acompound or a salt thereof according to claim 1 wherein R¹ is selectedfrom the group consisting of oxazolyl, pyrazolyl, pyridyl, pyridazinyl,and pyrimidinyl; wherein the oxazolyl, pyrazolyl, pyridyl, pyridazinyl,and pyrimidinyl may be unsubstituted or substituted by methyl, ethyl,halo or ═O.
 3. A compound or a salt thereof according to claim 1 whereinR¹ is pyridyl.
 4. A compound or a salt thereof according to claim 1wherein R² is methyl.
 5. A compound selected from the list consistingof:3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid; 3-(5-chloro-6-(pyridin-2-ylmethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(5-methylpyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-((5-fluoropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-((5-chloropyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-((5-methylpyridin-2-yl)methoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(oxazol-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(5-fluoropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(pyridazin-3-ylmethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(pyrimidin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(5-chloropyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-((6-methylpyridazin-3-yl)methoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(5-chloropyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(pyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(5-methylpyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoicacid;3-(5-chloro-6-(1-(pyridin-2-yl)propoxy)benzo[d]isoxazol-3-yl)propanoicacid; or a salt thereof.
 6. A compound selected from the list consistingof:3-{5-chloro-6-[1-(5-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(6-ethylpyridin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[(5-chloropyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[(5-methylpyrimidin-2-yl)methoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(2-methyl-1,3-oxazol-5-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(4-ethyl-1,3-oxazol-2-yl)ethoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(pyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoicacid3-{5-chloro-6-[1-(pyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(6-methylpyridazin-3-yl)propoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(5-methylpyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoicacid;3-{5-chloro-6-[1-(5-chloropyrimidin-2-yl)propoxy]-1,2-benzoxazol-3-yl}propanoicacid; and3-(5-chloro-6-(1-(1-ethyl-1H-pyrazol-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid; or a salt thereof
 7. A compound of formula (I) which is(R)-3-(5-chloro-6-(1-(pyridin-2-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid of formula

or a salt thereof.
 8. A compound of formula (I) which is(R)-3-(5-chloro-6-(1-(6-methylpyridazin-3-yl)ethoxy)benzo[d]isoxazol-3-yl)propanoicacid of formula

or a salt thereof.
 9. The compound of claim 7 as the free acid.
 10. Acompound as defined in claim 1 as a pharmaceutically acceptable saltthereof.
 11. A compound as defined in claim 1 as a pharmaceuticallyacceptable salt thereof, for use in therapy.
 12. A compound as definedin claim 11 for use in the treatment of a condition or disorder mediatedby KMO.
 13. A compound as defined in claim 12 for use in the treatmentof acute pancreatitis, chronic kidney disease, acute kidney disease,acute kidney injury, other conditions associated with systemicinflammatory response syndrome (SIRS), Huntington's disease, Alzheimer'sdisease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementiacomplex, HIV infection, amylotrophic lateral sclerosis (ALS),depression, schizophrenia, sepsis, cardiovascular shock, severe trauma,acute lung injury, acute respiratory distress syndrome, acutecholecystitis, severe burns, pneumonia, extensive surgical procedures,ischemic bowel, severe acute hepatic disease, severe acute hepaticencephalopathy or acute renal failure.
 14. (canceled)
 15. A method oftreatment of a condition or disaorder mediated by KMO, which methodcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (I) as defined in claim 1wherein the condition or disorder mediated by KMO is acute pancreatitis,chronic kidney disease, acute kidney disease, acute kidney injury, otherconditions associated with systemic inflammatory response syndrome(SIRS), Huntington's disease, Alzheimer's disease, spinocerebellarataxias, Parkinson's disease, AIDS-dementia complex, HIV infection,amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis,cardiovascular shock, severe trauma, acute lung injury, acuterespiratory distress syndrome, acute cholecystitis, severe burns,pneumonia, extensive surgical procedures, ischemic bowel, severe acutehepatic disease, severe acute hepatic encephalopathy or acute renalfailure.
 16. A method of treatment of a condition or disorder mediatedby KMO which method comprises administering to a patient in need thereofa therapeutically effective amount of a compound as defined in claim 1or a pharmaceutically acceptable salt thereof.
 17. A method of treatmentof acute pancreatitis, chronic kidney disease, acute kidney disease,acute kidney injury, other conditions associated with systemicinflammatory response syndrome (SIRS), Huntington's disease, Alzheimer'sdisease, spinocerebellar ataxias, Parkinson's disease, AIDS-dementiacomplex, HIV infection, amylotrophic lateral sclerosis (ALS),depression, schizophrenia, sepsis, cardiovascular shock, severe trauma,acute lung injury, acute respiratory distress syndrome, acutecholecystitis, severe burns, pneumonia, extensive surgical procedures,ischemic bowel, severe acute hepatic disease, severe acute hepaticencephalopathy or acute renal failure which method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 1 or a pharmaceuticallyacceptable salt thereof.
 18. A pharmaceutical composition comprising: a)a therapeutically effective amount of a compound of formula (I) asdefined in claim 1 or a pharmaceutically acceptable salt thereof; and b)a pharmaceutically acceptable excipient.
 19. A pharmaceuticalcomposition for use in the treatment of acute pancreatitis, chronickidney disease, acute kidney disease, acute kidney injury, otherconditions associated with systemic inflammatory response syndrome(SIRS), Huntington's disease, Alzheimer's disease, spinocerebellarataxias, Parkinson's disease, AIDS-dementia complex, HIV infection,amylotrophic lateral sclerosis (ALS), depression, schizophrenia, sepsis,cardiovascular shock, severe trauma, acute lung injury, acuterespiratory distress syndrome, acute cholecystitis, severe burns,pneumonia, extensive surgical procedures, ischemic bowel, severe acutehepatic disease, severe acute hepatic encephalopathy or acute renalfailure which comprises a therapeutically effective amount of a compoundof formula (I) as defined in claim 1 or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable excipient.